Glycosidase inhibitors

ABSTRACT

The disclosure relates to compounds of formula (I) useful in the treatment of tauopathies and Alzheimer&#39;s disease 
                         
wherein A, R, W, Q, n, and m are described herein.

RELATED APPLICATIONS

This application is a U.S. National Phase application, filed under 35U.S.C. § 371(c), of International Application No. PCT/EP2015/069598,filed Aug. 27, 2015, which claims the benefit of and priority to IndianPatent Application No. 2766/MUM/2014, filed Aug. 28, 2014, the entirecontents of each of which are incorporated herein by reference in theirentireties.

The present invention relates to a medicament comprising a compound offormula (I)

wherein A, R, W, Q, n and m have the meaning according to the claims,and/or physiologically acceptable salts, tautomers, solvates,stereoisomers and derivatives thereof. The compounds of formula (I) canbe used as glycosidase inhibitors. Objects of the invention are alsopharmaceutical compositions comprising the compounds of formula (I), andthe use of the compounds of formula (I) for the treatment of one or moretauopathies and Alzheimer's disease.

A wide range of cellular proteins, both nuclear and cytoplasmic, arepost-translationally modified by the addition of the monosaccharide2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetyl glucosamine) whichis attached via an O-glycosidic linkage. This modification is generallyreferred to as O-linked N-acetylglucosamine or O-GlcNAc. The enzymeresponsible for post-translationally linking β-N-acetylglucosamine(GlcNAc) to specific serine and threonine residues of numerousnucleocytoplasmic proteins is O-GlcNAc transferase (OGTase). A secondenzyme, known as O-GlcNAcase, removes this post-translationalmodification to liberate proteins making the O-GlcNAc-modification adynamic cycle occurring several times during the lifetime of a protein.

O-GlcNAc-modified proteins regulate a wide range of vital cellularfunctions including, for example, transcription, proteasomal degradationand cellular signaling. O-GlcNAc is also found on many structuralproteins. For example, it has been found on a number of cytoskeletalproteins, including neurofilament proteins, synapsins, synapsin-specificclathrin assembly protein AP-3 and Ankyrin-G. O-GlcNAc modification hasbeen found to be abundant in the brain. It has also been found onproteins clearly implicated in the etiology of several diseasesincluding tauopathies, Alzheimer's disease (AD), Parkinson's disease,and cancer.

For example, it is well established that AD and a number of relatedtauopathies including Progressive Supranuclear Palsy (PSP), Down'ssyndrome, Pick's disease, Niemann-Pick Type C disease and amyotrophiclateral sclerosis (ALS) are characterized, in part, by the developmentof neurofibrillary tangles (NFTs). These NFTs are aggregates of pairedhelical filaments (PHFs) and are composed of an abnormal form of thecytoskeletal protein “tau”. Normally, tau stabilizes a key cellularnetwork of microtubules that is essential for distributing proteins andnutrients within neurons. In AD patients, however, tau becomeshyperphosphorylated, disrupting its normal function, forming PHFs andultimately aggregating to form NFTs. Six isoforms of tau are found inthe human brain. In AD patients, all six isoforms of tau are found inNFTs, and all are markedly hyperphosphorylated. Tau in healthy braintissue bears only 2 or 3 phosphate groups, whereas those found in thebrains of AD patients bear, on average, 8 phosphate groups. A clearparallel between NFT levels in the brains of AD patients and theseverity of dementia strongly supports a key role for tau dysfunction inAD. The precise causes of this hyperphosphorylation of tau remainelusive. Accordingly, considerable effort has been dedicated toward: a)elucidating the molecular physiological basis of tauhyperphosphorylation; and b) identifying strategies that could limit tauhyperphosphorylation in the hope that these might halt, or even reverse,the progression of tauopathies and Alzheimer's disease. Several lines ofevidence suggest that up-regulation of a number of kinases may beinvolved in hyperphosphorylation of tau, although very recently, analternative basis for this hyperphosphorylation has been advanced.

In particular, it has recently emerged that phosphate levels of tau areregulated by the levels of O-GlcNAc on tau. The presence of O-GlcNAc ontau has stimulated studies that correlate O-GlcNAc levels with tauphosphorylation levels. The recent interest in this field stems from theobservation that O-GlcNAc modification has been found to occur on manyproteins at amino acid residues that are also known to bephosphorylated. Consistent with this observation, it has been found thatincreases in phosphorylation levels result in decreased O-GlcNAc levelsand conversely, increased O-GlcNAc levels correlate with decreasedphosphorylation levels. This reciprocal relationship between O-GlcNAcand phosphorylation has been termed the “Yin-Yang hypothesis” and hasgained strong biochemical support by the recent discovery that theenzyme OGTase forms a functional complex with phosphatases that act toremove phosphate groups from proteins. Like phosphorylation, O-GlcNAc isa dynamic modification that can be removed and reinstalled several timesduring the lifespan of a protein. Suggestively, the gene encodingO-GlcNAcase has been mapped to a chromosomal locus that is linked to AD.Hyperphosphorylated tau in human AD brains has markedly lower levels ofO-GlcNAc than are found in healthy human brains. Very recently, it hasbeen shown that O-GlcNAc levels of soluble tau protein from human brainsaffected with AD are markedly lower than those from healthy brain.Furthermore, PHF from diseased brain was suggested to lack completelyany O-GlcNAc modification whatsoever. The molecular basis of thishypoglycosylation of tau is not known, although it may stem fromincreased activity of kinases and/or dysfunction of one of the enzymesinvolved in processing O-GlcNAc. Supporting this latter view, in bothPC-12 neuronal cells and in brain tissue sections from mice, anonselective N-acetylglucosaminidase inhibitor was used to increase tauO-GlcNAc levels, whereupon it was observed that phosphorylation levelsdecreased. Moreover, it has been described that the O-GlcNAcmodification of tau directly inhibits its aggregation without perturbingthe conformational properties of tau monomers. The implication of thesecollective results is that by maintaining healthy O-GlcNAc levels in ADpatients, such as by inhibiting the action of O-GlcNAcase (OGA), oneshould be able to block hyperphosphorylation of tau and all of theassociated effects of tau hyperphosphorylation, including the formationof NFTs and downstream effects. However, because the proper functioningof the lysosomal β-hexosaminidases is critical, any potentialtherapeutic intervention for the treatment of AD that blocks the actionof O-GlcNAcase would have to avoid the concomitant inhibition of bothlysosomal hexosaminidases A and B.

Consistent with the known properties of the hexosamine biosyntheticpathway, the enzymatic properties of O-GlcNAc transferase (OGTase), andthe reciprocal relationship between O-GlcNAc and phosphorylation, it hasbeen shown that decreased glucose availability in brain leads to tauhyperphosphorylation. The gradual impairment of glucose transport andmetabolism leads to decreased O-GlcNAc and hyperphosphorylation of tau(and other proteins). Accordingly, the inhibition of O-GlcNAcase shouldcompensate for the age-related impairment of glucose metabolism withinthe brains of health individuals as well as patients suffering from ADor related neurodegenerative diseases.

These results suggest that a malfunction in the mechanisms regulatingtau O-GlcNAc levels may be vitally important in the formation of NFTsand associated neurodegeneration. Good support for blocking tauhyperphosphorylation as a therapeutically useful intervention comes fromstudies showing that when transgenic mice harboring human tau aretreated with kinase inhibitors, they do not develop typical motordefects and, in another case, show a decreased level of insoluble tau.These studies provide a clear link between lowering tau phosphorylationlevels and alleviating AD-like behavioral symptoms in a murine model ofthis disease.

There is also a large body of evidence indicating that increased levelsof O-GlcNAc protein modification provides protection against pathogeniceffects of stress in cardiac tissue, including stress caused byischemia, hemorrhage, hypervolemic shock, and calcium paradox. Forexample, activation of the hexosamine biosynthetic pathway (HBP) byadministration of glucosamine has been demonstrated to exert aprotective effect in animal models of ischemia/reperfusion, traumahemorrhage, hypervolemic shock and calcium paradox. Moreover, strongevidence indicates that these cardioprotective effects are mediated byelevated levels of protein O-GlcNAc modification. There is also evidencethat the O-GlcNAc modification plays a role in a variety ofneurodegenerative diseases, including Parkinson's disease and relatedSynucleinopathies, and Huntington's disease.

Humans have three genes encoding enzymes that cleave terminalβ-N-acetyl-glucosamine residues from glycoconjugates. The first of theseencodes the enzymeO-glycoprotein-2-acetamido-2-deoxy-β-D-glucopyranosidase (O-GlcNAcase).O-GlcNAcase is a member of family 84 of glycoside hydrolases.O-GlcNAcase acts to hydrolyze O-GlcNAc off of serine and threonineresidues of post-translationally modified proteins. Consistent with thepresence of O-GlcNAc on many intracellular proteins, the enzymeO-GlcNAcase appears to have a role in the etiology of several diseasesincluding type II diabetes, AD and cancer. Although O-GlcNAcase waslikely isolated earlier on, about 20 years elapsed before itsbiochemical role in acting to cleave O-GlcNAc from serine and threonineresidues of proteins was understood. More recently O-GlcNAcase has beencloned, partially characterized, and suggested to have additionalactivity as a histone acetyltransferase.

However, a major challenge in developing inhibitors for blocking thefunction of mammalian glycosidases, including O-GlcNAcase, is the largenumber of functionally related enzymes present in tissues of highereukaryotes. Accordingly, the use of non-selective inhibitors in studyingthe cellular and organismal physiological role of one particular enzymeis complicated because complex phenotypes arise from the concomitantinhibition of such functionally related enzymes. In the case ofβ-N-acetylglucosaminidases, existing compounds that act to blockO-GlcNAcase function are non-specific and act potently to inhibit thelysosomal β-hexosaminidases.

Low molecular weight OGA inhibitors are e.g. disclosed in theinternational applications WO 2008/025170 and WO 2014/032187. However,no OGA inhibitor has reached the market yet. Thus, there is still a needfor low molecular weight molecules that selectively inhibit OGA.

U.S. Pat. No. 3,489,757. mentions i.a. the following compounds:

(1-[1-(1,3-benzodioxol-5-yl)ethyl]-4-(4-methyl-2-thiazolyl)-piperazine(example 144) and2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-4-methylthiazole)

U.S. Pat. No. 3,485,757 teaches the respective compounds for thetreatment of hypertension and does not relate to the use in thetreatment of neurodegenerative diseases, stress, cancer or diabetes orto OGA inhibitor activity.

U.S. Pat. No. 3,299,067 discloses compounds as medicaments, inparticular as peripheral vasodilators, analgesics and anti-inflammatoryagents. U.S. Pat. No. 3,299,067 does not disclose any OGA inhibitoractivity. The compounds of U.S. Pat. No. 3,299,067 bear a methylenegroup in the bridging position. U.S. Pat. No. 3,299,067 does not referto any OGA inhibitor activity.

WO 99/21850 discloses compounds that bind to the dopamine D4 receptorsubtype and are said to be useful in treatment of variousneuropsychological disorders. However, the compounds are not active asOGA inhibitors. For example, compound 5 of WO 99/21850 shows thefollowing data, when measured according to Example B01 of the presentapplication (Human O-GlcNAcase enzyme inhibition assay):

Compounds that modulate MCH binding to MCH receptors are presented in WO2005/110982. The compounds are said to be useful in the treatment ofeating disorders, sexual disorders, diabetes, heart disease, and stroke,which are unrelated to the indications of the present invention. Thecompounds are not active as OGA inhibitors. For instance, the compoundof example 72 of WO 2005/110982 provides the following data, whenmeasured according to Example B01 of the present application:

WO 2009/053373 discloses molecules for the treatment of PARP-mediateddisorders, such as neurodegenerative diseases. The molecules of WO2009/053373 are not useful as OGA inhibitors. For instance, the compoundof example 56 of WO 99/21850 shows the following data, when measuredaccording to Example B01 of the present application:

The present invention has the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

It has been surprisingly found that the compounds according to theinvention and salts thereof have very valuable pharmacologicalproperties. In particular, they act as glycosidase inhibitors. Theinvention relates to compounds of formula (I)

wherein

-   R is straight chain or branched alkyl having 1 to 6 carbon atoms,    wherein 1 to 5 hydrogen atoms may be replaced by Hal or OH.    Preferably R is methyl, CH₂OH, CF₃, CHF₂, CH₂F;-   W is CH or N, preferably N;-   A denotes one of the following groups:

-   X is N or CR′″. Preferably all or one or two of X in a group are CH;-   X¹, X² is N or CR′″;-   X³ is N or CR′″″-   Y is O, S, SO or SO₂. Preferably Y is O or S;-   R′, R″ denote each independently H, Hal or straight chain or    branched alkyl having 1 to 12 carbon atoms. Preferably both are    either H, F or methyl;-   R′″, R″″ independently denote H, Hal, NR³R⁴, CHR³R⁴, OR³, CN,    straight chain or branched alkyl having 1 to 12 carbon atoms,    wherein 1 to 3 CH₂-groups may be replaced by a group selected from    O, NR³, S, SO, SO₂, CO, COO, OCO, CONR³, NR³CO and wherein 1 to 5    hydrogen atoms may be replaced by Hal, NR³R⁴ or NO₂. Preferably both    R′″ and/or R″″ are H, Hal, NR³R⁴, CHR³R⁴, OR³, CN or alkyl;-   R′″″ denotes H, Hal, NR³R⁴, CHR³R⁴, CN, straight chain or branched    alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH₂-groups may be    replaced by a group selected from O, NR³, S, SO, SO₂, CO, COO, OCO,    CONR³, NR³CO and wherein 1 to 5 hydrogen atoms may be replaced by    Hal, NR³R⁴ or NO₂. Preferably, R′″″ is H, Hal or alkyl;-   R³, R⁴ denote each independently H or a straight chain or branched    alkyl group having 1 to 12 carbon atoms, preferably H, methyl or    ethyl;-   Q denotes one of the following groups:

-   Z¹ is S, O, NR³;-   Z², Z³ independently denote CR⁵ or N;-   Z^(2′) is CR^(5′) or N;-   T is N, CH or CR⁷;-   R⁵, R⁶, R⁷ independently denote H, Hal, NR³R⁴, NO₂, straight chain    or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3    CH₂-groups may be replaced by a group selected from O, NR³, S, SO,    SO₂, CO, COO, OCO, CONR³, NR³CO and wherein 1 to 5 hydrogen atoms    may be replaced by Hal, NR³R⁴, NO₂, OR³, Het, Ar, Cyc, or denote Ar,    Het or Cyc;-   R^(5′) denotes H, Hal, NR³R⁴, NO₂, a straight chain or branched    alkyl having 2 to 12 carbon atoms, or a straight chain or branched    alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH₂-groups are    replaced by a group selected from O, NR³, S, SO, SO₂, CO, COO, OCO,    CONR³, NR³CO and/or wherein 1 to 5 hydrogen atoms are replaced by    Hal, NR³R⁴, NO₂, OR³, Het, Ar, Cyc, or R^(5′) denotes Ar, Het or    Cyc; R^(5′) may also denote methyl, in cases where R is other than    methyl and/or W is CH and/or A is other than

-    and/or n or m are 0, 2 or 3 and/or Z¹ is O or NR³ and/or Z² is N    and/or Z³ is CR⁵ and/or R⁵ is other than H and/or the compound of    formula I is not a racemate;-   R⁸ denotes H, methyl or straight chain or branched alkyl having 2 to    12 carbon atoms, wherein 1 to 3 CH₂-groups may be replaced by a    group selected from O, NR³, S, SO, SO₂, CO, COO, OCO, CONR³, NR³CO    and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR³R⁴ or    NO₂;-   Hal denotes F, Cl, Br or I, preferably F, Cl or Br;-   Het denotes a saturated, unsaturated or aromatic ring, being    monocyclic or bicyclic or fused-bicyclic and having 3- to 8-members    and containing 1 to 4 heteroatoms selected from N, O and S, which    may be substituted by 1 to 3 substituents selected from R⁵, Hal and    OR³;-   Ar denotes a 6-membered carbocyclic aromatic ring or a fused or    non-fused bicylic aromatic ring system, which is optionally    substituted by 1 to 3 substituents independently selected from R⁵,    OR³ and Hal;-   Cyc denotes a saturated carbocyclic ring having from 3 to 8 carbon    atoms which is optionally substituted by 1 to 3 substituents    independently selected from R⁵ or Hal or OH;-   m and n denote independently from one another 0, 1, 2 or 3    and pharmaceutically usable derivatives, solvates, salts, prodrugs,    tautomers, enantiomers, racemates and stereoisomers thereof,    including mixtures thereof in all ratios and compounds of formula I,    wherein one or more H atoms are replaced by D (deuterium).

Specifically, formula (I) includes the following two enantiomers offormula Ia and Ib:

wherein A, R, W, Q, n and m have the meaning given above.

Throughout the specification, R in formula I, Ia and Ib is preferablymethyl. The indices m and n in formula I, Ia and Ib are preferablysimultaneously 1.

Most preferably, compounds of formula I are the compounds of formula Aand B:

If individual groups, such as T, occurs more than once in a compound offormula I, it can have the same or different meanings according to therespective definition of that group.

Preferred compounds of the present invention are preferably used intheir non-racemic form, i.e. as enantiomerically pure compounds or theirenantiomerically enriched mixtures of the enantiomers. If R is anunsubstituted straight chain or branched alkyl having 1 to 6 carbonatoms, such as methyl, ethyl, n-propyl or iso-butyl, the S-enantiomersof compounds of formula I are preferred. Very preferred are formulae Iband B.

In general, compounds of formula I are preferred that contain one oremore preferred groups such as R′ to R′″″ or R³ to R⁷ or indices such asm or n. Compounds of formula I are the more preferred, the morepreferred groups or indices they contain.

If substituents, such as the group R⁸, are connected to the remainder ofthe molecule through a heteroatom, the connecting atom in the respectivegroup is preferably a carbon atom or the respective group is H.

The invention also relates to the use of compounds of formula (I) as amedicament.

In the meaning of the present invention, the compound is defined toinclude pharmaceutically usable derivatives, solvates, prodrugs,tautomers, enantiomers, racemates and stereoisomers thereof, includingmixtures thereof in all ratios.

The term “pharmaceutically usable derivatives” is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds. The term “solvates” of the compounds istaken to mean adductions of inert solvent molecules onto the compounds,which are formed owing to their mutual attractive force. Solvates are,for example, mono- or dihydrates or alkoxides. The invention alsocomprises solvates of salts of the compounds according to the invention.The term “prodrug” is taken to mean compounds according to the inventionwhich have been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the effective compounds according to the invention. These alsoinclude biodegradable polymer derivatives of the compounds according tothe invention. It is likewise possible for the compounds of theinvention to be in the form of any desired prodrugs such as, forexample, esters, carbonates, carbamates, ureas, amides or phosphates, inwhich cases the actually biologically active form is released onlythrough metabolism. Any compound that can be converted in-vivo toprovide the bioactive agent (i.e. compounds of the invention) is aprodrug within the scope and spirit of the invention. Various forms ofprodrugs are well known in the art. It is further known that chemicalsubstances are converted in the body into metabolites which may whereappropriate likewise elicit the desired biological effect—in somecircumstances even in more pronounced form. Any biologically activecompound that was converted in-vivo by metabolism from any of thecompounds of the invention is a metabolite within the scope and spiritof the invention.

The compounds of the invention may be present in the form of theirdouble bond isomers as pure E or Z isomers, or in the form of mixturesof these double bond isomers. Where possible, the compounds of theinvention may be in the form of the tautomers, such as keto-enoltautomers. All stereoisomers of the compounds of the invention arecontemplated, either in a mixture or in pure or substantially pure form.The compounds of the invention can have asymmetric centers at any of thecarbon atoms. Consequently, they can exist in the form of theirracemates, in the form of the pure enantiomers and/or diastereomers orin the form of mixtures of these enantiomers and/or diastereomers. Themixtures may have any desired mixing ratio of the stereoisomers. Thus,for example, the compounds of the invention which have one or morecenters of chirality and which occur as racemates or as diastereomermixtures can be fractionated by methods known per se into their opticalpure isomers, i.e. enantiomers or diastereomers. The separation of thecompounds of the invention can take place by column separation on chiralor non-chiral phases or by re-crystallization from an optionallyoptically active solvent or with use of an optically active acid or baseor by derivatization with an optically active reagent such as, forexample, an optically active alcohol, and subsequent elimination of theradical.

The invention also relates to the use of mixtures of the compoundsaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.These are particularly preferably mixtures of stereoisomeric compounds.

An enantiomerically enriched mixture denotes a compound of Formula (I)or related formula having an enantiomeric excess, as measured by methodswell known by one skilled in the art, of 10% or more, preferably 50% ormore, and more preferably more than 95%. Most preferably anenantiomerically enriched mixture denotes a compound of Formula (I) orrelated Formulae having an enantiomeric excess of more than 98%.

The nomenclature as used herein for defining compounds, especially thecompounds according to the invention, is in general based on the rulesof the IUPAC-organization for chemical compounds and especially organiccompounds. The compounds of invention have been named according to thestandards used in the program AutoNom 2000 or ACD Lab Version 12.01. Thedetermination of the stereochemistry (S) or (R) is performed usingstandard rules of the nomenclature well known by one skilled in the art.The terms indicated for explanation of the above compounds of theinvention always, unless indicated otherwise in the description or inthe claims, have the following meanings:

The term “unsubstituted” means that the corresponding radical, group ormoiety has no substituents. The term “substituted” means that thecorresponding radical, group or moiety has one or more substituents.Where a radical has a plurality of substituents, and a selection ofvarious substituents is specified, the substituents are selectedindependently of one another and do not need to be identical. Eventhough a radical has a plurality of a specific-designated substituentthe expression of such substituent may differ from each other (e.g.methyl and ethyl). It shall be understood accordingly that a multiplesubstitution by any radical of the invention may involve identical ordifferent radicals. Hence, if individual radicals occur several timeswithin a compound, the radicals adopt the meanings indicated,independently of one another.

The term “alkyl” or “alkyl group” refers to acyclic saturated orunsaturated hydrocarbon radicals, which may be branched orstraight-chain and preferably have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10carbon atoms, i.e. C₁-C₁₀-alkanyls. Examples of suitable alkyl radicalsare methyl, ethyl, n-propyl, isopropyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-,1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, n-pentyl,iso-pentyl, neo-pentyl, tert-pentyl, 1-, 2-, 3- or -methyl-pentyl,n-hexyl, 2-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl,n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl,n-icosanyl, n-docosanyl.

In an embodiment of the invention, A denotes unbranched or branchedalkyl having 1-10 C atoms, in which 1-7H atoms may be replacedindependently from one another by Hal. A preferred embodiment of Adenotes unbranched or branched alkyl having 1-6 C atoms, in which 1-4atoms may be replaced independently from one another by Hal. In a morepreferred embodiment of the invention, A denotes unbranched or branchedalkyl having 1-4 C atoms, in which 1-3H atoms can be replacedindependently from one another by Hal, particularly by F and/or Cl. Itis most preferred that A denotes unbranched or branched alkyl having 1-6C atoms. Highly preferred is C₁₋₄-alkyl. A C₁₋₄-alkyl radical is forexample a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, 1,1,1-trifluoroethyl or bromomethyl, especiallymethyl, ethyl, propyl or trifluoromethyl. It shall be understood thatthe respective denotation of A is independently of one another in anyradical of the invention.

The terms “cycloalkyl” or “Cyc” for the purposes of this inventionrefers to saturated and partially unsaturated non-aromatic cyclichydrocarbon groups/radicals, having 1 to 3 rings, that contain 3 to 20,preferably 3 to 12, more preferably 3 to 9 carbon atoms. The cycloalkylradical may also be part of a bi- or polycyclic system, where, forexample, the cycloalkyl radical is fused to an aryl, heteroaryl orheterocyclyl radical as defined herein by any possible and desired ringmember(s). The bonding to the compounds of the general formula (I) canbe effected via any possible ring member of the cycloalkyl radical.Examples of suitable cycloalkyl radicals are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl,cyclohexenyl, cyclopentenyl and cyclooctadienyl.

In an embodiment of the invention, Cyc denotes cycloalkyl having 3-7 Catoms, in which 1-4H atoms may be replaced independently of one anotherby Hal. Preferred is C₃-C₇-cycloalkyl. More preferred isC₄-C₇-cycloalkyl. Most preferred is C₅-C₇-cycloalkyl, i.e. cyclopentyl,cyclohexyl or cycloheptyl, highly preferably cyclohexyl. It shall beunderstood that the respective denotation of Cyc is independently of oneanother in any radical of the invention.

The term “aryl” or “carboaryl” for the purposes of this invention refersto a mono- or polycyclic aromatic hydrocarbon systems having 3 to 14,preferably 3-12, more preferably 4 to 12, most preferably 5 to 10,highly preferably 6 to 8 carbon atoms, which can be optionallysubstituted. The term “aryl” also includes systems in which the aromaticcycle is part of a bi- or polycyclic saturated, partially unsaturatedand/or aromatic system, such as where the aromatic cycle is fused to anaryl, cycloalkyl, heteroaryl or heterocyclyl group as defined herein viaany desired and possible ring member of the aryl radical. The bonding tothe compounds of the general formula (I) can be effected via anypossible ring member of the aryl radical. Examples of suited arylradicals are phenyl, biphenyl, naphthyl, 1-naphthyl, 2-naphthyl andanthracenyl, but likewise indanyl, indenyl or1,2,3,4-tetrahydronaphthyl. Preferred carboaryls of the invention areoptionally substituted phenyl, naphthyl and biphenyl, more preferablyoptionally substituted monocylic carboaryl having 6-8 C atoms, mostpreferably optionally substituted phenyl.

Ar and aryl are preferably selected from the following group: phenyl,o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl,o-, m- or p-isopropylphenyl, o-, m- or p-tert.-butylphenyl, o-, m- orp-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl,o-, m- or p-fluoro-phenyl, o-, m- or p-bromophenyl, o-, m- orp-chlorophenyl, o-, m- or p-sulfonamidophenyl, o-, m- orp-(N-methyl-sulfonamido)phenyl, o-, m- orp-(N,N-dimethyl-sulfonamido)-phenyl, o-, m- orp-(N-ethyl-N-methyl-sulfonamido)phenyl, o-, m- orp-(N,N-diethyl-sulfonamido)-phenyl, particularly 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl,2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl or 2,5-dimethyl-4-chlorophenyl.

Irrespective of further substitutions, Het denotes preferably 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazoM-, -4- or -5-yl, 1,2,4-triazo-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-iso-5indolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzo-pyrazolyl, 2-, 4-,5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-,5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-,5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8- quinazolinyl, 5- or6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, furtherpreferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4-, -5-yl or 2,1,3-benzoxadiazol-5-yl,azabicyclo-[3.2.1]octyl or dibenzofuranyl.

The heterocyclic radicals may also be partially or fully hydrogenated.

Irrespective of further substitutions, Het can thus also denote,preferably, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-,-4- or 5-furyl, tetra-hydro-2- or -3-furyl, 1,3-dioxolan-4-yl,tetrahydro-2- or -3-thienyl, 2,3-di-hydro-1-, -2-, -3-, -4- or-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1- , 2- or3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-,-2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl,1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,-4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl,1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl,hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl,1,2,3,4-tetrahydro-1-(-2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl,1,2,3,4-tetra-hydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl,2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermorepreferably 2,3-methylene-dioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydro-benzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-di-hydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2,3-dihydrobenzimidazolyl.

Het preferably denotes piperidinyl, 4-hydroxypiperidinyl, piperazinyl,4-methylpiperazinyl, pyrrolidinyl, morpholinyl, dihydro-pyrazolyl,dihydro-pyridyl, dihydropyranyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, benzimidazolyl,benzotriazolyl, indolyl, benzo-1,3-dioxolyl,2,3-dihydro-benzo[1,4]dioxinyl, indazolyl or benzothiadiazolyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted.

The term “halogen”, “halogen atom”, “halogen substituent” or “Hal” forthe purposes of this invention refers to one or, where appropriate, aplurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl,chloro) or iodine (I, iodo) atoms. The designations “dihalogen”,“trihalogen” and “perhalogen” refer respectively to two, three and foursubstituents, where each substituent can be selected independently fromthe group consisting of fluorine, chlorine, bromine and iodine. Halogenpreferably means a fluorine, chlorine or bromine atom. Fluorine andchlorine are more preferred, particularly when the halogens aresubstituted on an alkyl (haloalkyl) or alkoxy group (e.g. CF₃ and CF₃O).It shall be understood that the respective denotation of Hal isindependently of one another in any radical of the invention.

R is preferably straight chain alkyl having 1 to 4 carbon atoms, wherein1 to 5 hydrogen atoms may be replaced by Hal or OH. More preferably R ismethyl or ethyl, and most preferably methyl.

W is preferably N.

A preferably denotes one of the following groups:

A is especially preferred one of the following groups:

Q is preferably

R⁵, R^(5′), R⁶ are preferably independently H, Hal, NR³R⁴, NO₂, phenyl,2-, 3- or 4-hydroxy or methoxyphenyl, alkyl, preferably methyl, ethyl,isopropyl, isobutyl, tert-butyl, CF₃, alkoxy (Oalkyl), preferablymethoxy or ethoxy, hydroxyalkylen, preferably CH₂OH, alkoxyalkylenpreferably CH₂OCH₃, COOH, COOalkyl, preferably COOCH₃, COOCH₂CH₃,CONHalkyl, preferably CONHCH₃, CONHCH₂CH₃, CONHisopropyl,CONHcyclohexyl, CONH₂, CON(CH₃)₂, NHCOalkyl, preferably NHCOCH₃,NHCOCH₂CH₃, NHCOPropyl, NHCOisopropyl, NHCOcyclopropyl,NHCO-4-Chloro-phenyl, NHCH₂CH₃, NHCH₂CH₂CH₃, NHCOCH₂CH₂OH,CO—N-morpholinyl, CON(CH₃)CH₂CH₂N(CH₃)₂, CO-1-piperidinyl,CO-4-hydroxy-1-piperidinyl, CO-1-piperazinyl, CO-4-methyl-1-piperazinyl,CH₂—N-morpholinyl, CH₂N(H)COCH₃, CH₂N(CH₃)COCH₃, CH₂NH₂, NH₂, CH(OH)CH₃,CH(OR³)CH₃

Most preferably, one of R⁵, R⁶ is H.

R⁷ has preferably the meaning of R⁵ and R⁶. More preferably, R⁷ is H,OCH₃, CH₃, CH₂CH₃, CF₃, Hal, preferably Cl, I, F, NH₂, NO₂, CONHalkyl,preferably CONHCH₃, CON(CH₃)₂, NHCOalkyl such as NHCOCH₃, NHalkyl, suchas NHCH₂CH₂CH₃, COOalkyl, preferably COOCH₂CH₃, hydroxyalkylen,preferably CH₂OH, CH(CH₃)OH, C(CH₃)₂OH, cyclohexyl, cyclopentyl,morpholinyl, tetrahydrofuranyl. Preferably cyclohexyl, cyclopentyl,morpholinyl, tetrahydrofuranyl are substituted by OH. Most preferredare:

R⁸ is preferably H, COalkyl or alkyl. More preferably, R⁸ is H, COmethylor methyl.

Most preferably, m and n simultaneously denote 1.

Accordingly, the subject-matter of the invention relates to compounds offormula (I) as medicament, in which at least one of the aforementionedradicals has any meaning, particularly realize any preferred embodiment,as described above. Radicals, which are not explicitly specified in thecontext of any embodiment of formula (I), sub-formulae thereof or otherradicals thereto, shall be construed to represent any respectivedenotations according to formula (I) as disclosed hereunder for solvingthe problem of the invention. That means that the aforementionedradicals may adopt all designated meanings as each described in theprior or following course of the present specification, irrespective ofthe context to be found, including, but not limited to, any preferredembodiments. It shall be particularly understood that any embodiment ofa certain radical can be combined with any embodiment of one or moreother radicals.

Particularly highly preferred embodiments are those compounds of formula(I) listed in Table 1 and/or physiologically acceptable salts thereof.

TABLE 1 Compounds of formulae (I). OGA enzyme inhibition assay:Configuration OGA No Structure specification IC50 (M)  1

Racemic ++  2

Racemic ++  3

Racemic +  4

Racemic ++  5

Racemic ++  6

Racemic +  7

Racemic ++  8

Racemic +++  9

Racemic ++  10

Racemic ++  11

Racemic +++  12

Racemic ++  13

Racemic ++  14

Racemic ++  15

Chiral HPLC Method C: 2nd eluting compound +++  16

Racemic +  17

Racemic ++  18

Racemic +++  19

Racemic ++  20

Racemic ++  21

Racemic ++  22

Racemic +++  23

Racemic +++  24

Racemic +++  25

Racemic +++  26

Chiral HPLC Method D: 2nd eluting compound +++  27

Racemic ++  28

Racemic +++  29

Racemic +++  30

Racemic +++  31

Racemic +++  32

Racemic ++  33

Racemic ++  34

Chiral HPLC Method D: 2nd eluting compound ++++  35

Racemic +++  36

Racemic +++  37

Racemic ++++  38

Racemic +++  39

Racemic +++  40

Racemic +++  41

Racemic +++  42

Racemic ++  43

Racemic +++  44

Racemic ++++  45

Racemic ++  46

Racemic +++  47

Racemic +++  48

Racemic ++++  49

Racemic ++  50

Racemic +++  51

Racemic +++  52

Racemic ++++  53

Racemic ++  54

Racemic +++  55

Racemic +++  56

Chiral HPLC Method E: 2nd eluting compound ++++  57

Chiral HPLC Method E: 2nd eluting compound ++++  58

Racemic +++  59

Chiral HPLC Method D: 1st eluting compound +  60

Chiral HPLC Method D: 2nd eluting compound +++  61

Chiral HPLC Method D: 2nd eluting compound +++  62

Chiral HPLC Method A: 1st eluting compound +++  63

Chiral HPLC Method D: 1st eluting compound +  64

Chiral HPLC Method D: 2nd eluting compound ++++  65

Chiral HPLC Method D: 1st eluting compound +  66

Chiral HPLC Method D: 2nd eluting compound ++++  67

Racemic +++  68

Chiral HPLC Method D: 1st eluting compound +  69

Chiral HPLC Method D: 2nd eluting compound ++++  70

Racemic ++  71

Chiral HPLC Method D: 2nd eluting compound ++++  72

Racemic ++++  73

Racemic +++  74

Chiral HPLC Method D: 1st eluting compound +  75

Chiral HPLC Method D: 2nd eluting compound ++++  76

Racemic +  77

Chiral HPLC Method L: 1st eluting compound +  78

Chiral HPLC Method L: 2nd eluting compound ++++  79

Racemic +++  80

Racemic ++++  81

Chiral HPLC Method B: 2nd eluting compound ++++  82

Racemic +++  83

Racemic +++  84

Racemic +++  85

Racemic ++++  86

Racemic ++++  87

Racemic +  88

Racemic +  89

Chiral HPLC Method D: 2nd eluting compound ++++  90

Racemic ++  91

Racemic +++  92

Racemic +++  93

Racemic ++++  94

Racemic ++  95

Chiral HPLC Method D: 2nd eluting compound +++  96

Racemic ++++  97

Racemic ++++  98

Racemic ++++  99

Racemic ++++ 100

Racemic ++ 101

Racemic ++ 102

Racemic +++ 103

Racemic +++ 104

Chiral HPLC Method L: 2nd eluting compound +++ 105

Racemic ++++ 106

Racemic ++++ 107

Racemic ++++ 108

Racemic ++++ 109

Racemic ++++ 110

Racemic +++ 111

Racemic +++ 112

Racemic +++ 113

Racemic +++ 114

Racemic ++++ 115

Racemic +++ 116

Racemic ++++ 117

Racemic ++ 118

Racemic ++ 119

Racemic +++ 120

Racemic +++ 121

Racemic + 122

Racemic ++++ 123

Racemic ++++ 124

Racemic + 125

Racemic + 126

Racemic ++ 127

Racemic + 128

Racemic ++++ 129

Racemic ++++ 130

Racemic ++ 131

Racemic + 132

S configuration; synthesized from Intermediate 16 ++++ 133

Chiral HPLC Method D: 2nd eluting compound ++++ 134

S configuration; synthesized from Intermediate 16 ++++ 135

Racemic + 136

S configuration; synthesized from Intermediate 16 ++ 137

S configuration; synthesized from Intermediate 16 ++++ 138

S configuration; synthesized from Intermediate 16 + 139

S configuration; synthesized from Intermediate 16 +++ 140

Racemic ++ 141

S configuration; synthesized from Intermediate 16 +++ 142

S configuration; synthesized from Intermediate 16 +++ 143

R configuration; synthesized from Intermediate 24 144

Racemic ++ 145

146

147

148

Racemic +++ 149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

Racemic ++ 166

Racemic +++ 167

Racemic ++++ 168

Racemic ++++ 169

Racemic ++++ 170

Racemic ++++ 171

S configuration; synthesized from Intermediate 16 ++++ 172

Racemic +++ 173

S configuration; synthesized from Intermediate 16 ++++ 174

Racemic + 175

S configuration; synthesized from Intermediate 16 ++++ 176

S configuration; synthesized from Intermediate 16 ++++ 177

S configuration; synthesized from Intermediate 16 ++++ 178

Racemic ++ 179

Racemic + 180

S configuration; synthesized from Intermediate 16 ++++ 181

S configuration; synthesized from Intermediate 16 ++++ 182

S configuration; synthesized from Intermediate 16 ++++ 183

S configuration; synthesized from Intermediate 16 +++ 184

S configuration; synthesized from Intermediate 16 ++++ 185

S configuration; synthesized from Intermediate 16 ++++ 186

S configuration; synthesized from Intermediate 16 ++++ 187

S configuration; synthesized from Intermediate 16 ++++ 188

S configuration; synthesized from Intermediate 16 ++++ 189

S configuration; synthesized from Intermediate 16 ++++ 190

S configuration; synthesized from Intermediate 16 ++++ 191

S configuration; synthesized from Intermediate 16 +++ 192

S configuration; synthesized from Intermediate 16 ++++ 193

S configuration; synthesized from Intermediate 16 ++++ 194

S configuration; synthesized from Intermediate 16 ++++ 195

S configuration; synthesized from Intermediate 16 ++++ 196

Racemic +++ 197

Chiral HPLC Method J: 2nd eluting compound ++++ 198

Chiral HPLC Method J: 1st eluting compound ++++ 199

Racemic +++ 200

Racemic +++ 201

Racemic + 202

Racemic Activity range of the compounds of Formula (I) is thefollowing: + 1 to 10 μM ++ 0.2 to 1 μM +++ 0.2 to 0.05 μM ++++ below0.05 μM

As can be seen above, a number of compounds according to formula I arevery potent OGA inhibitors, for example compounds of example 34 (inparticular the second eluting compound(S)-2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)pyrimidine),37, 44, 48, 52, 56 (the second eluting compound(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide),69 (the second eluting compound(S)-N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide),72 and 75 (the second eluting compound(S)-(2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-methylpiperazin-1-yl)methanone),114, 116, 128, 129, 132, 134, 137, 168, 173, 176, 180, 181, 182.

Preferred compounds of the present invention demonstrate adequateproperties for use as a drug. In particular such preferred compoundsshow a high solid state stability, high stability in the presence ofliver microsome, high oxidation stability and suitable permeability.Further preferred compounds of the present invention demonstrate theirsuitability as drugs by potent biological activity, such as the level ofO-GlcNAcylation of total proteins measured in brain extracts. Relevanttests for determining such parameters are known by the person skilled inthe art, e.g. solid state stability (Waterman K. C. (2007) Pharm Res24(4); 780-790), stability in the presence of liver microsome (Obach R.S. (1999) Drug Metab Dispos 27(11); 1350-135) and the permeability (e.g.Caco-2 permeability assay, Calcagno A. M. (2006) Mol Pharm 3(1); 87-93);alternatively, they are described in Examples below, such as Example B02describing the determination of O-GlcNAcylation level of total proteinsmeasured in brain extracts. Compounds of the present invention that showa high potency in OGA inhibition assays and one or more of the aboveproperties are especially suitable as a drug for the indicationsmentioned in the present specification.

The compounds according to formula (I) and the starting materials forits preparation, respectively, are produced by methods known per se, asdescribed in the literature, i.e. under reaction conditions that areknown and suitable for said reactions.

Use can also be made of variants that are known per se, but are notmentioned in greater detail herein. If desired, the starting materialscan also be formed in-situ by leaving them in the un-isolated status inthe crude reaction mixture, but immediately converting them further intothe compound according to the invention. On the other hand, it ispossible to carry out the reaction stepwise.

The following abbreviations refer respectively to the definitions below:

Ac (acetyl), aq (aqueous), h (hour), g (gram), L (liter), mg(milligram), MHz (Megahertz), μM (micromolar), min (minute), mm(millimeter), mmol (millimole), mM (millimolar), m.p. (melting point),equiv (equivalent), mL (milliliter), μL (microliter), ACN(acetonitrile), AcOH (acetic acid), BINAP(2,2′-bis(disphenylphosphino)-1,1′-binaphthalene, BOC(tert-butoxy-carbonyl), CBZ (carbobenzoxy), CDCl₃ (deuteratedchloroform), CD₃OD (deuterated methanol), CH₃CN (acetonitrile), c-hex(cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane),dppf (1,1′-bis(diphenylphosphino)ferrocene), DIC (diisopropylcarbodiimide), DIEA (diisopropylethylamine), DMF (dimethylformamide),DMSO (dimethylsulfoxide), DMSO-d₆ (deuterated dimethylsulfoxide), EDC(1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electro-sprayionization), EtOAc (Ethyl acetate), Et₂O (diethyl ether), EtOH(ethanol), FMOC (fluorenylmethyloxycarbonyl), HATU(dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluorophosphate), HPLC (High Performance Liquid Chromatography),i-PrOH (2-propanol), K₂CO₃ (potassium carbonate), LC (LiquidChromatography), MD Autoprep (Mass directed Autoprep), MeOH (methanol),MgSO₄ (magnesium sulfate), MS (mass spectrometry), MTBE (Methyltert-butyl ether), Mtr. (4-Methoxy-2,3,6-trimethylbenzensulfonyl), MW(microwave), NBS (N-bromo succinimide), NaHCO₃ (sodium bicarbonate),NaBH₄ (sodium borohydride), NMM (N-methyl morpholine), NMR (NuclearMagnetic Resonance), POA (phenoxyacetate), Py (pyridine), PyBOP®(benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate), RT (room temperature), Rt (retention time), SFC(supercritical fluid chromatography), SPE (solid phase extraction), T3P(propylphosphonic anhydride), TBAF (tetra-n-butylammonium fluoride),TBTU (2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluromium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF(tetrahydrofurane), TLC (Thin Layer Chromatography), UV (Ultraviolet).

In general, the compounds according to Formula (I) and related formulaeof this invention may be prepared from readily available startingmaterials. If such starting materials are not commercially available,they may be prepared by standard synthetic techniques. In general, thesynthesis pathways for any individual compound of Formula (I) andrelated formulae will depend on the specific substituents of eachmolecule, such factors being appreciated by those having ordinary skillin the art. The following general methods and procedures describedhereinafter in the examples may be employed to prepare compounds ofFormula (I) and related formulae. Reaction conditions depicted in thefollowing schemes, such as temperatures, solvents, or co-reagents, aregiven as examples only and are not restrictive. It will be appreciatedthat where typical or preferred experimental conditions (i.e. reactiontemperatures, time, moles of reagents, solvents etc.) are given, otherexperimental conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvents used, but such conditions can be determined by a person skilledin the art, using routine optimisation procedures. For all theprotection and deprotection methods, see Philip J. Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and,Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in OrganicSynthesis”, Wiley Interscience, 3^(rd) Edition 1999.

A “leaving group” LG denotes a chemical moiety which can be removed orreplaced by another chemical group. Throughout the specification, theterm leaving group preferably denotes Cl, Br, I or a reactively modifiedOH group, such as, for example, an activated ester, an imidazolide oralkylsulfonyloxy having 1 to 6 carbon atoms (preferablymethylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6 to 10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).When a leaving group LG is attached to an aromatic or heteroaromaticring, LG can denote in addition SO₂-alkyl or F. Radicals of this typefor activation of the carboxyl group in typical acylation reactions aredescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart). Activated esters areadvantageously formed in situ, for example through addition of HOBt,N-hydroxysuccinimide or HATU.

Depending on the nature of A, R, W, Q, m and n, different syntheticstrategies may be selected for the synthesis of compounds of Formula(I). In the process illustrated in the following schemes, A, R, W, Q, mand n are as above-defined in the description unless otherwisementioned.

Compounds of Formula (I), wherein A, R, W, Q, m and n are defined asabove, can be prepared from alternative compounds of Formula (I), usingsuitable interconversion procedures such as those described hereinafterin the examples, or conventional interconversion procedures well knownby one skilled in the art.

Compound of formula (I) can be separated into compounds of formula (Ia)and (Ib) by chiral chromatography or by chiral resolution,re-crystallization with use of an optically active acid, using methodsknown by one skilled in the art and as described below in the examples(Scheme 1).

Compounds of formula (Ic), wherein A, R, Q, m and n are defined as aboveand W═N, can be prepared by the addition of an amine of formula (II) toa heterocycle of formula (III), where LG is a leaving group as definedabove. This addition can be performed under thermic conditions, heatingboth compounds at a temperature between 50° C. and 200° C., usingregular heating or microwave irradiation, in the presence of a base,such as but not limited to TEA, DIEA, K₂CO₃ or Cs₂CO₃, in a polarsolvent, e.g. DMF, DMA or NMP. Alternatively, this addition can becatalysed by a metal complex, such as but not limited to PdCl₂,Pd(OAc)₂, Pd₂(dba)₃ in the presence of a ligand, e.g. BINAP, o-Tol₃P,X-Phos, and a base, e.g. NaOtBu, Cs₂CO₃ or K₂CO₃, in a suitable solventor solvent mixture, for example dioxane, Toluene/MeOH, at a temperaturebetween RT to 150° C., preferably at RT, for a few hours, e.g. one hourto 24 h (Scheme 2). Amine of formula (II) is obtained after deprotectionof compound (IVa). PG is a suitable protecting group, which iscompatible with the chemistry described below, such as but not limitedto BOC. It can be removed under acidic conditions, such as but notlimited to HCl in MeOH or dioxane or TFA in DCM, yielding isolation ofamine (II).

Compounds of formula (Id), wherein A, R, Q, m and n are defined as aboveand W═CH, can be prepared from an ester (IVb) using method known by aperson killed in the art and as described in the examples below.Different heterocycles Q can be prepared from ester functionality, suchas but not limited to oxadiazole, thiadiazole and thiazole, (Jakopin, Z.et al. Curr. Org. Chem. 2008, 12, 850-898. Hemming, K. Science ofSynthesis, 2004, 13, 127-184. Augustine, J. K. et al. Tetrahedron, 2009,65, 9989-9996. 37. Kempson, J. Name Reactions in Heterocyclic ChemistryII (2011), 299-308). Depending on the nature of Q, compound of formula(Id) can be obtained from compound (IVc) by displacement of the leavinggroup LG, as defined above, in the presence of a base such as but notlimited to Cs₂CO₃ in a polar solvent, e.g. DMF, DMSO or NMP (Scheme 3).Alternatively compound of formula (Id) can be prepared by metalcatalysed cross coupling reaction with a suitable boronic acid (Va) orester (Vb) and an heterocycle of formula (III), using conditions knownby a person skilled in the art, such as but not limited to Pd(PPh₃)₄ ascatalyst, K₂CO₃ as base, dioxane as solvent at temperature ranging fromRT to 180° C. (Scheme 3). Hydrogenation of the resulting couplingproduct in the presence of a catalyst such as Pd(OH)₂, would yieldcompound of formula (Id) (e.g. Andres, J.-I. et al. J. Med. Chem. 2012,55, 8685-8699) (Scheme 3).

Compound of formula (IV), wherein A, R, W, Q, m and n are defined asabove and Y¹ is a protecting group PG when W═N or an ester when W═CH,can be prepared from the corresponding ketone (IX) by reductiveamination with amine (VI), using conditions known to the one skilled inthe art, such as but not limited to the use of NaBH(OAc)₃ as reducingagent, in the presence of one equivalent of AcOH in DCE. Alternatively,reductive amination can be performed in two steps, with first imineformation, that can be catalysed by Ti(OiPr)₄, followed by reductionwith suitable reducing agent, such as but not limited to NaBH₄ in MeOH(Abdel-Magid, A. F. at al. J. Org. Chem. 1996, 61, 3849-3862).Alternatively, ketone (IX) can be reduced into the corresponding alcohol(VIII) using usual reductive agents such as NaBH₄ in an alcoholicsolvent, such as MeOH. Alcohol functionality can be then transformedinto a suitable leaving group, such as but not limited to Cl or OMs,using conditions known to a person skilled in the art. The addition ofamine (VI) to intermediate (VII) would yield the formation of compound(IV).

Alternatively, compound of formula (X), wherein W, Q, m and n aredefined as above and PG is a suitable protecting group, such as but notlimited to BOC, can be prepared from amine (XI), from compounds (XII),wherein m, n and PG are defined as above and Y² is an ester or a leavinggroup, or from compounds (XIIIa) or (XIIIb) (Scheme 5).

When W is N, compound of formula (X) can be prepared by the addition ofan amine of formula (XI) to a heterocycle of formula (III), where LG isa leaving group as defined above. This addition can be performed underthermic conditions or can be catalysed by a metal complex, usingconditions known by a person skilled in the art and as described belowin the examples.

When W is CH, compound of formula (X) can be prepared from an ester(XII), wherein Y²═COOR and W═CH, using method known by a person skilledin the art and as described in the examples below. Differentheterocycles Q can be prepared from ester functionality, such as but notlimited to oxadiazole, thiadiazole and thiazole, (Jakopin, Z. et al.Curr. Org. Chem. 2008, 12, 850-898. Hemming, K. Science of Synthesis,2004, 13, 127-184. Augustine, J. K. et al. Tetrahedron, 2009, 65,9989-9996. 37. Kempson, J. Name Reactions in Heterocyclic Chemistry II(2011), 299-308). Depending on the nature of Q, compound of formula (X)can be obtained from compound (XII), wherein W is CH and Y²=LG asdefined above, by displacement of the leaving group LG in the presenceof a base such as but not limited to Cs₂CO₃ in a polar solvent, e.g.DMF, DMSO or NMP.

Compound of formula (X), wherein Q is a thiazole, can be obtained fromcompound (XII), wherein Y² is an aminomethanecarbothioyl group, and asuitable alpha-bromo ketone, using conditions know by a person skilledin the art.

Alternatively, compound of formula (X) can be prepared by metalcatalysed cross coupling reaction with a suitable boronic acid (XIIIa)or ester (XIIIb), and a heterocycle of formula (III), using conditionsknown by a person skilled in the art, such as but not limited toPd(PPh₃)₄ as catalyst, K₂CO₃ as base, dioxane as solvent at temperatureranging from RT to 180° C. (Scheme 5). Hydrogenation of the resultingcoupling product in the presence of a catalyst such as Pd(OH)₂, wouldyield compound of formula (X) (e.g. Andres, J.-I. et al. J. Med. Chem.2012, 55, 8685-8699) (Scheme 5).

PG is a suitable protecting group, which is compatible with thechemistry described above, such as but not limited to BOC. It can beremoved under acidic conditions, such as but not limited to HCl in MeOHor dioxane or TFA in DCM, yielding isolation of amine (XIV). It can befurther transformed into compound of formula (I) by reductive alkylationwith ketone of formula (IX), following conditions well known by a personskilled in the art, as described in the examples (Abdel-Magid, A. F. atal. J. Org. Chem. 1996, 61, 3849-3862). Alternatively, amine (XIV)addition to compound (VII), prepared as described above and in theexamples, would yield the formation of compound of formula (I).

Amine of formula (II) can be separated into amines of formula (IIa) and(IIb) by chiral chromatography or chiral resolution byre-crystallization with an optically active acid, using methods known byone skilled in the art and as described below in the examples (Scheme6).

Alternatively, amines of formula (IIa) and (IIb) can be synthesized fromchiral amines (XVIa) and (XVIb) respectively. Addition of amines (XVIa)and (XVIb) to reagent (XV), wherein PG is a protecting group, e.g. BOCor SO₂Tol and LG is a leaving group, e.g. Cl, would yield the formationof protected amines (IVe) and (IVf) respectively (Thiel, O. R. et al. J.Org. Chem. 2008, 73, 3508-3515). Deprotection conditions need to beselected based on the nature of the PG, such as HCl in dioxane or MeOHor TFA in DCM for BOC protecting group. Alternatively a mixture of HBr,AcOH and 4-hydroxybenzoic acid or a mixture of H₂SO₄ and trifluoroaceticacid at temperatures ranging from RT to 100° C. would be used to cleavea sulfonamide protecting group, such as para-toluene sulfonamide.

For the preparation of amines of formula (XVIa) and (XVIb), ketone offormula (IX) can be transformed into chiral imine (XVIII), reacting witha chiral auxiliary, such as but not limited to tert-butanesulfinamidegroup in the presence of titanium ethoxide (Ellman J. A. et al. Acc.Chem. Res. 2002, 35, 984-995). It can be further transformed intosulfinamide (XVIIa) or (XVIIb), depending on the conditions used for thereduction step, as described in the reference from Ellman J. A. et al.J. Org. Chem. 2007, 72, 626-629.

Alternatively aldehyde of formula (XIX) can be transformed into alcoholof formula (VIII) with addition of a suitable nucleophile, such as butnot limited to a Grignard reagent (Scheme 9).

In another process, ketone of formula (IXa) can be obtained by Stillecross coupling reaction between aryl halide (XX) andtributyl(1-ethoxyvinyl)tin in the presence of a catalyst, such as butnot limited to Pd(PPh₃)₂Cl₂ in toluene at temperatures ranging from RTto 110° C. (Scheme 10).

When a reaction is preferably performed under basic conditions, asuitable base might be selected from metal oxides, e.g. aluminum oxide,alkaline metal hydroxide (potassium hydroxide, sodium hydroxide andlithium hydroxide, inter alia), alkaline earth metal hydroxide (bariumhydroxide and calcium hydroxide, inter alia), alkaline metal alcoholates(potassium ethanolate and sodium propanolate, inter alia), alkalinemetal carbonates (e.g., sodium bicarbonate) and several organic bases(e.g., N,N-diisopropylethylamine, piperidine or diethanolamine, interalia).

The reaction is generally carried out in an inert solvent. Suitableinert solvents are, for example, hydrocarbons, such as hexane, petroleumether, benzene, toluene or xylene; chlorinated hydrocarbons, such astrichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroformor dichloromethane; alcohols, such as methanol, ethanol, isopropanol,n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether,diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, suchas ethylene glycol monomethyl or monoethyl ether, ethylene glycoldimethyl ether (diglyme); ketones, such as acetone or butanone; amides,such as acetamide, dimethylacetamide or dimethylformamide (DMF);nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); carbon disulfide; carboxylic acids, such as formic acid, aceticacid or trifluoroacetic acid (TFA); nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents. Particular preference is given to TFA, DMF,dichloromethane, THF, H₂O, methanol, tert. butanol, tert. amylalcohol,triethylamine or dioxane.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −80° C.and 140° C., normally between −50° C. and 120° C., preferably between−20° C. and 100° C.

The present invention also relates to a process for manufacturingcompounds of formula (I) comprising the steps of:

The compounds of formula (I) and sub-formulae thereof are accessible viathe routes above. The starting materials, are usually known to theskilled artisan, or they can be easily prepared by known methods.

The compounds of formula (I) can be modified, like hydrogenated ormetal-reduced, to remove the chlorine, or put into a substitutionreaction, and/or to be transformed with an acid or base into a salt,preferably with a strong acid. Numerous papers and methods are availableand useful for the one skilled in the art in respect for organicchemistry, chemical strategies and tactics, synthetic routes, protectionof intermediates, cleavage and purification procedure, isolation andcharacterization. General chemical modifications are known to the oneskilled in the art. Halogenation of aryls or hydroxy substitution byhalogens of acids, alcohols, phenols, and their tautomeric structurescan be preferably carried out by use of POCl₃, or SOCl₂, PCl₅, SO₂Cl₂.In some instances oxalyl chloride is also useful. Temperatures can varyfrom 0° C. to reflux depending on the task to halogenate a pyridonestructure or a carboxylic acid or a sulfonic acid. Time will also beadjusted from minutes to several hours or even over night. Similarly,alkylation, ether formation, ester formation, amide formation are knownto the one skilled in the art. Arylation with aryl boronic acids can beperformed in presence of a Pd catalyst, appropriate ligand and base,preferably a carbonate, phosphate, borate salt of sodium, potassium orcesium. Organic bases, like Et₃N, DIPEA or the more basic DBU can alsobe used. Solvents can vary too, from toluene, dioxane, THF, diglyme,monoglyme, alcohols, DMF, DMA, NMP, acetonitrile, in some cases evenwater, and others. Commonly used catalysts like Pd (PPh₃)₄, or Pd(OAc)₂,PdCl₂ type precursors of PdO catalysts have advanced to more complexones with more efficient ligands. In C—C arylations, instead of boronicacids and esters, aryl-trifluoroborate potassium salts (Suzuki-Miyauracoupling), organo silanes (Hiyama coupling), Grignard reagents (Kumada),organozinc compounds (Negishi coupling) and stannanes (Stille coupling)may be useful. This experience can be transferred to N- andO-arylations. Numerous papers and methods are available and useful forthe one skilled in the art in respect of N-arylation and even ofelectron deficient anilines, and with aryl chlorides and anilines aswell as for O-arylation by using Cu catalysis and Pd catalysis.

In the final step of the processes above, a salt of the compounds,preferably those of formula (I), is optionally provided. The saidcompounds according to the invention can be used in their final non-saltform. On the other hand, the present invention also encompasses the useof these compounds in the form of their pharmaceutically acceptablesalts, which can be derived from various organic and inorganic acids andbases by procedures known in the art. Pharmaceutically acceptable saltforms of the compounds according to the invention are for the most partprepared by conventional methods. If the compound according to theinvention contains a carboxyl group, one of its suitable salts can beformed by the reaction of the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as magnesiumhydroxide, calcium hydroxide and barium hydroxide; alkali metalalkoxides, for example potassium ethoxide and sodium propoxide; andvarious organic bases, such as piperidine, diethanolamine andN-methyl-glucamine (meglumine), benzathine, choline, diethanolamine,ethylenediamine, benethamine, diethylamine, piperazine, lysine,L-arginine, ammonia, triethanolamine, betaine, ethanolamine, morpholineand tromethamine. The aluminum salts of the compounds according to theinvention are likewise included. In the case of certain compounds of theformula I, which contain a basic center, acid-addition salts can beformed by treating these compounds with pharmaceutically acceptableorganic and inorganic acids, for example hydrogen halides, such ashydrogen chloride, hydrogen bromide or hydrogen iodide, other mineralacids and corresponding salts thereof, such as sulfate, nitrate orphosphate and the like, and alkyl- and monoarylsulfonates, such asmethanesulfonate, ethanesulfonate, toluenesulfonate andbenzenesulfonate, and other organic acids and corresponding saltsthereof, such as carbonate, acetate, trifluoroacetate, tartrate,maleate, succinate, citrate, benzoate, salicylate, ascorbate and thelike. Accordingly, pharmaceutically acceptable acid-addition salts ofthe compounds according to the invention include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprate, caprylate, chloride, chlorobenzoate, citrate,cyclamate, cinnamate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, glycolate, fumarate, galacterate (from mucic acid),galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate,hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,iodide, isethionate, isobutyrate, lactate, lactobionate, malate,maleate, malonate, mandelate, metaphosphate, methanesulfonate,methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, oleate, palmoate, pectinate, persulfate,phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate,but this does not represent a restriction.

Both types of salts may be formed or interconverted preferably usingion-exchange resin techniques.

With regard to that stated above, it can be seen that the expressions“pharmaceutically acceptable salt” and “physiologically acceptablesalt”, which are used interchangeable herein, in the present connectionare taken to mean an active ingredient which comprises a compoundaccording to the invention in the form of one of its salts, inparticular if this salt form imparts improved pharmacokinetic propertieson the active ingredient compared with the free form of the activeingredient or any other salt form of the active ingredient used earlier.The pharmaceutically acceptable salt form of the active ingredient canalso provide this active ingredient for the first time with a desiredpharmacokinetic property which it did not have earlier and can even havea positive influence on the pharmacodynamics of this active ingredientwith respect to its therapeutic efficacy in the body.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, me-glumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tro-meth-amine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula (I) areprepared by bringing the free base form into contact with a sufficientamount of the desired acid, causing the formation of the salt in aconventional manner. The free base can be regenerated by bringing thesalt form into contact with a base and isolating the free base in aconventional manner. The free base forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts other-wise correspond tothe respective free base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanol-amine, ethylenediamine, N-methyl-D-glucamine and procaine.This is not intended to represent a restriction.

The base-addition salts of acidic compounds of the formula I areprepared by bringing the free acid form into contact with a sufficientamount of the desired base, causing the formation of the salt in aconventional manner. The free acid can be regenerated by bringing thesalt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts other-wise correspond tothe respective free acid forms thereof.

If a compound of the formula (I) contains more than one group which iscapable of forming pharmaceutically acceptable salts of this type, theformula I also encompasses multiple salts. Typical multiple salt formsinclude, for example, bitartrate, diacetate, difumarate, dimeglumine,di-phosphate, disodium and trihydrochloride, but this is not intended torepresent a restriction.

With regard to that stated above, it can be seen that the expressions“pharmaceutically acceptable salt” and “physiologically acceptablesalt”, which are used interchangeable herein, in the present connectionare taken to mean an active ingredient which comprises a compoundaccording to the invention in the form of one of its salts, inparticular if this salt form imparts improved pharmacokinetic propertieson the active ingredient compared with the free form of the activeingredient or any other salt form of the active ingredient used earlier.The pharmaceutically acceptable salt form of the active ingredient canalso provide this active ingredient for the first time with a desiredpharmacokinetic property which it did not have earlier and can even havea positive influence on the pharmacodynamics of this active ingredientwith respect to its therapeutic efficacy in the body.

Owing to their molecular structure, the compounds of the formula (I) canbe chiral and can accordingly occur in various enantiomeric forms. Theycan therefore exist in racemic or in optically active form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theIntermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the (R)and (S) forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaricacid, di-O-p-toluoyl-tartaric acid, mandelic acid, malic acid, lacticacid, suitable N-protected amino acids (for example N-benzoylproline orN-benzenesulfonylproline), or the various optically activecamphorsulfonic acids. The suitably formed salt with optically activeacid is crystallized using various combinations of solvents, such as butnot limited to methanol, ethanol, isopropanol, THF, water, diethylether, acetone, methyl tert-butyl ethers and other solvents known to theperson skilled in the art. Also advantageous is chromatographicenantiomer resolution with the aid of an optically active resolvingagent (for example dinitrobenzoylphenylglycine, cellulose triacetate orother derivatives of carbohydrates or chirally derivatised methacrylatepolymers immobilised on silica gel). Suitable eluents for this purposeare aqueous or alcoholic solvent mixtures, such as, for example,hexane/isopropanol/acetonitrile, for example in the ratio 82:15:3.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimize pharmacokinetic parameters whileretaining desirable in-vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In-vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula (I) with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula (I) are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concentration at maximum therapeutic effect(C_(max)), area under the dose response curve (AUC), and F; and in termsof reduced clearance, dose and materials costs.

A further aspect of the invention relates to the use of compoundsaccording to formula (I) and/or physiologically acceptable salts thereoffor inhibiting a glycosidase. Such use may be therapeutic ornon-therapeuic in character. The term “inhibition” denotes any reductionin glycosidase activity, which is based on the action of the specificinventive compounds capable to interact with the target glycosidase insuch a manner that makes recognition, binding and blocking possible. Itshall be understood that the compounds of the invention finally interactwith the target to unfold the effect. The compounds are characterized bysuch an appreciable affinity to at least one glycoside hydrolase whichensures a reliable binding and preferably a complete blocking ofglycosidase activity. More preferably, the substances are mono-specificin order to guarantee an exclusive and directed recognition with thechosen single glycosidase target. In the context of the presentinvention, the term “recognition”—without being limited thereto—relatesto any type of interaction between the specific compounds and thetarget, particularly covalent or non-covalent binding or association,such as a covalent bond, hydrophobic/hydrophilic interactions, van derWaals forces, ion pairs, hydrogen bonds, ligand-receptor interactions,and the like. Such association may also encompass the presence of othermolecules such as peptides, proteins or nucleotide sequences. Thepresent receptor/ligand-interaction is preferably characterized by highaffinity, high selectivity and minimal or even lacking cross-reactivityto other target molecules to exclude unhealthy and harmful impacts tothe treated subject.

In a preferred embodiment of the present invention, the glycosidasecomprises glycoside hydrolases, more preferably family 84 glycosidehydrolases, most preferablyO-glycoprotein-2-acetamido-2deoxy-β-D-glucopyranosidase (OGA), highlypreferably a mammalian O-GlcNAcase. It is particularly preferred thatthe compounds of formula (I) according to the invention selectively bindan O-GlcNAcase, e.g. thereby selectively inhibiting the cleavage of2-acetamido-2-deoxy-β-D-glucopyranoside (O-GlcNAc) while they do notsubstantially inhibit a lysosomal β-hexosaminidase.

The compounds according to the invention preferably exhibit anadvantageous biological activity, which is easily demonstrated in enzymeactivity assays as described herein or known from prior art. In suchin-vitro assays, the compounds preferably exhibit and cause aninhibitory effect. IC₅₀ is the concentration of a compound that produces50% of the maximal inhibition for that compound. The glycosidase targetis especially half inhibited by the compounds described herein if theconcentration of the compounds amounts to less than 100 μM, preferablyless than 10 μM, more preferably less than 1 μM, most preferably lessthan 0.2 μM. Most preferably, compounds of Formula (I) exhibit an IC₅₀less than 0.02 μM.

A further aspect of the present invention relates to a method forinhibiting a glycosidase, wherein a system capable of expressing theglycosidase, particularly expressing said glycosidase, is contacted withat least one compound of formula (I) according to the invention and/orphysiologically acceptable salts thereof, under conditions such thatsaid glycosidase is inhibited. In a preferred embodiment of the method,the glycosidase is contacted with a compound selectively inhibitingO-GlcNAcase and more preferably having an IC₅₀ of less than 0.2 μM. Itis also preferred that the method is performed in-vitro and/or that themethod is not practiced on the human body. A cellular system ispreferred in the scope of the method. The cellular system is defined tobe any subject provided that the subject comprises cells. The cellrefers to any type of primary cells or genetically engineered cells,whether in the isolated status, in culture, as cell line, assembled intissue, organs or intact laboratory mammals, provided that they arecapable of expressing the glycosidase. It shall also be understood thatthe cell expresses the glycosidase as inherent pre-condition to put themethods of inhibition into practice. Although it is particularlypreferred that the cells are capable of expressing or do express theglycosidase, it shall not be excluded that glycosidase-deficient cellscan be used and the glycosidase is artificially added to the cellularsystem. The assay of the invention can be even completely performedin-vitro such that the cell is waived but a glycosidase is contactedwith at least one compound of formula (I) according to the inventionand/or physiologically acceptable salts thereof. Hence, an amount ofisolated glycosidase is provided in crude or purified form for thispurpose.

As discussed herein, the glycosidase-signaling pathways are relevant forvarious diseases, preferably neurodegenerative diseases, diabetes,cancer and stress. Accordingly, the compounds according to the inventionare useful in the prophylaxis and/or treatment of diseases that aredependent on the said signaling pathways by interaction with one or moreof them. The present invention therefore relates to the therapeutic andnon-therapeutic use of compounds according to the invention asinhibitors of the signaling pathways described herein, preferably of theOGA-mediated signaling.

The method of the invention can be performed either in-vitro or in-vivo.The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be particularly determined by in-vitrotests, whether in the course of research or clinical application.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to modulate glycosidase activity,usually between about one hour and one week. In-vitro treatment can becarried out using cultivated cells from any sample or cell line.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models and models of transgenic animals. For thedetermination of certain stages in the signal transduction cascade,interacting compounds can be utilized in order to modulate the signal.The compounds according to the invention can also be used as reagentsfor testing OGA-dependent signal transduction pathways in animals and/orcell culture models or in the clinical diseases mentioned in thisapplication.

The use according to the previous paragraphs of the specification may beeither performed in-vitro or in-vivo models. The inhibition can bemonitored by the techniques described in the course of the presentspecification. The in-vitro use is preferably applied to samples ofhumans suffering from neurodegenerative diseases, diabetes, cancer andstress. Testing of several specific compounds and/or derivatives thereofmakes the selection of that active ingredient possible that is bestsuited for the treatment of the human subject. The in-vivo dose rate ofthe chosen derivative is advantageously pre-adjusted to the glycosidasesusceptibility and/or severity of disease of the respective subject withregard to the in-vitro data. Therefore, the therapeutic efficacy isremarkably enhanced. Moreover, the subsequent teaching of the presentspecification concerning the use of the compounds according to formula(I) and its derivatives for the production of a medicament for theprophylactic or therapeutic treatment and/or monitoring is considered asvalid and applicable without restrictions to the use of the compound forthe inhibition of glycosidase activity, preferably OGA activity, ifexpedient.

A further aspect of the invention relates to a medicament comprising atleast one compound according to the invention and/or pharmaceuticallyusable derivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios. A “medicament” in the meaning of theinvention is any agent in the field of medicine, which comprises one ormore compounds of formula (I) or preparations thereof (e.g. apharmaceutical composition or pharmaceutical formulation) and can beused in prophylaxis, therapy, follow-up or aftercare of patients whosuffer from diseases, which are associated with OGA activity, in such away that a pathogenic modification of their overall condition or of thecondition of particular regions of the organism could establish at leasttemporarily.

Consequently, the invention also relates to a pharmaceutical compositioncomprising as active ingredient an effective amount of at least onecompound of formula (I) according to the invention and/orphysiologically acceptable salts thereof together with pharmaceuticallytolerable adjuvants and/or excipients.

In the meaning of the invention, an “adjuvant” denotes every substancethat enables, intensifies or modifies a specific response against theactive ingredient of the invention if administered simultaneously,contemporarily or sequentially. Known adjuvants for injection solutionsare, for example, aluminum compositions, such as aluminum hydroxide oraluminum phosphate, saponins, such as QS21, muramyldipeptide ormuramyltripeptide, proteins, such as gamma-interferon or TNF, M59,squalen or polyols.

Furthermore, the active ingredient may be administered alone or incombination with other treatments. A synergistic effect may be achievedby using more than one compound in the pharmaceutical composition, i.e.the compound of formula (I) is combined with at least another agent asactive ingredient, which is either another compound of formula (I) or acompound of different structural scaffold. The active ingredients can beused either simultaneously or sequentially. The present compounds aresuitable for combination with agents known to those of skill in the art(e.g., WO 2008/025170) and are useful with the compounds of theinvention.

In some embodiments, a compound according to the invention, or for useaccording to the invention, may be provided in combination with anyother active agents or pharmaceutical compositions where such combinedtherapy may be useful to modulate O-GlcNAcase activity, for example totreat neurodegenerative, inflammatory, cardiovascular, orimmunoregulatory diseases or any condition described herein. In someembodiments, a compound according to the invention, or for use accordingto the invention, may be provided in combination with one or more agentsuseful in the prevention or treatment of tauopathies and Alzheimer'sdisease. Examples of such agents may include, without limitation,

-   -   Acetylcholine esterase inhibitors (AChEIs) such as Aricept®        (Donepezil), Exelon® (Rivastigmine), Razadyne® (Razadyne ER®,        Reminyl®, Nivalin®, Galantamine), Cognex® (Tacrine), Huperzine        A, Phenserine, Debio-9902 SR (ZT-1 SR), Zanapezil (TAK0147),        ganstigmine, NP7557, α7 nicotinic acetylcholine receptor        agonists, 5-HT6 receptor antagonists, etc    -   Tau aggregation inhibitors such as methylene blue, etc    -   Microtubule stabilizers such as AL-108, AL-208, paclitaxel, etc    -   Amyloid-β (A β) peptide lowering agents such as β-secretase        (BACE-1) inhibitors, senile plaque-clearing biologics such as Aβ        antibodies and Aβ vaccines

The invention also relates to a set (kit) consisting of separate packsof an effective amount of a compound according to the invention and/orpharmaceutically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient. The setcomprises suitable containers, such as boxes, individual bottles, bagsor ampoules. The set may, for example, comprise separate ampoules, eachcontaining an effective amount of a compound according to the inventionand/or pharmaceutically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilized form.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intra-dermal) methods. Such formulationscan be prepared using processes known in the pharmaceutical art by,e.g., combining the active ingredient with the excipient(s) oradjuvant(s).

The pharmaceutical composition of the invention is produced in a knownway using common solid or liquid carriers, diluents and/or additives andusual adjuvants for pharmaceutical engineering and with an appropriatedosage. The amount of excipient material that is combined with theactive ingredient to produce a single dosage form varies depending uponthe host treated and the particular mode of administration. Suitableexcipients include organic or inorganic substances that are suitable forthe different routes of administration, such as enteral (e.g. oral),parenteral or topical application, and which do not react with compoundsof formula (I) or salts thereof. Examples of suitable excipients arewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatin, carbohydrates, e.g. lactose orstarch, magnesium stearate, talc and petroleum jelly.

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multi-dose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilized) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavors.

In a preferred embodiment of the present invention, the pharmaceuticalcomposition is adapted for oral administration. The preparations can besterilized and/or can comprise auxiliaries, such as carrier proteins(e.g. serum albumin), lubricants, preservatives, stabilizers, fillers,chelating agents, antioxidants, solvents, bonding agents, suspendingagents, wetting agents, emulsifiers, salts (for influencing the osmoticpressure), buffer substances, colorants, flavorings and one or morefurther active substances, for example one or more vitamins. Additivesare well known in the art, and they are used in a variety offormulations.

Accordingly, the invention also relates to a pharmaceutical compositioncomprising as active ingredient an effective amount of at least onecompound of formula (I) according to the invention and/orphysiologically acceptable salts thereof together with pharmaceuticallytolerable adjuvants for oral administration, optionally in combinationwith at least another active pharmaceutical ingredient. The priorteaching of the present specification concerning administration routeand combination product, respectively, is valid and applicable withoutrestrictions to the combination of both features if expedient.

The terms “effective amount” or “effective dose” or “dose” areinterchangeably used herein and denote an amount of the pharmaceuticalcompound having a prophylactically or therapeutically relevant effect ona disease or pathological conditions, i.e. which causes in a tissue,system, animal or human a biological or medical response which is soughtor desired, for example, by a researcher or physician. A “prophylacticeffect” reduces the likelihood of developing a disease or even preventsthe onset of a disease. A “therapeutically relevant effect” relieves tosome extent one or more symptoms of a disease or returns to normalityeither partially or completely one or more physiological or biochemicalparameters associated with or causative of the disease or pathologicalconditions. In addition, the expression “therapeutically effectiveamount” denotes an amount which, compared with a corresponding subjectwho has not received this amount, has the following consequence:improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder. Theexpression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The respective dose or dosage range for administering the pharmaceuticalcomposition according to the invention is sufficiently high in order toachieve the desired prophylactic or therapeutic effect of reducingsymptoms of the aforementioned diseases. It will be understood that thespecific dose level, frequency and period of administration to anyparticular human will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general state of health, gender, diet, time and route of administration,rate of excretion, drug combination and the severity of the particulardisease to which the specific therapy is applied. Using well-known meansand methods, the exact dose can be determined by one of skill in the artas a matter of routine experimentation. The prior teaching of thepresent specification is valid and applicable without restrictions tothe pharmaceutical composition comprising the compounds of formula (I)if expedient.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. The concentration of the prophylactically ortherapeutically active ingredient in the formulation may vary from about0.1 to 100 wt %. Preferably, the compound of formula (I) or thepharmaceutically acceptable salts thereof are administered in doses ofapproximately 0.5 to 1000 mg, more preferably between 1 and 700 mg, mostpreferably 5 and 100 mg per dose unit. Generally, such a dose range isappropriate for total daily incorporation. In other terms, the dailydose is preferably between approximately 0.02 and 100 mg/kg of bodyweight. The specific dose for each patient depends, however, on a widevariety of factors as already described in the present specification(e.g. depending on the condition treated, the method of administrationand the age, weight and condition of the patient). Preferred dosage unitformulations are those which comprise a daily dose or part-dose, asindicated above, or a corresponding fraction thereof of an activeingredient. Furthermore, pharmaceutical formulations of this type can beprepared using a process which is generally known in the pharmaceuticalart.

Although a therapeutically effective amount of a compound according tothe invention has to be ultimately determined by the treating doctor orvet by considering a number of factors (e.g. the age and weight of theanimal, the precise condition that requires treatment, severity ofcondition, the nature of the formulation and the method ofadministration), an effective amount of a compound according to theinvention for the treatment of neurodegenerative diseases, for exampletauopathies and Alzheimer's disease, is generally in the range from 0.1to 100 mg/kg of body weight of the recipient (mammal) per day andparticularly typically in the range from 1 to 10 mg/kg of body weightper day. Thus, the actual amount per day for an adult mammal weighing 70kg is usually between 70 and 700 mg, where this amount can beadministered as a single dose per day or usually in a series ofpart-doses (such as, for example, two, three, four, five or six) perday, so that the total daily dose is the same. An effective amount of asalt or solvate or of a physiologically functional derivative thereofcan be determined as the fraction of the effective amount of thecompound according to the invention per se. It can be assumed thatsimilar doses are suitable for the treatment of other conditionsmentioned above.

The pharmaceutical composition of the invention can be employed asmedicament in human and veterinary medicine. According to the invention,the compounds of formula (I) and/or physiologically salts thereof aresuited for the prophylactic or therapeutic treatment and/or monitoringof diseases that are caused, mediated and/or propagated by OGA activity.It is particularly preferred that the diseases are neurodegenerativediseases, diabetes, cancer and stress, more preferably neurodegenerativediseases, most preferably one or more tauopathies, highly preferablyAlzheimer's disease and dementia. It shall be understood that the hostof the compound is included in the present scope of protection accordingto the present invention.

Another aspect of the present invention relates to compounds of formula(I) according to the invention and/or physiologically acceptable saltsthereof for use in the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byOGA activity. Another aspect of the invention concerns compounds offormula (I) according to the invention and/or physiologically acceptablesalts thereof for use in the prophylactic or therapeutic treatmentand/or monitoring of neurodegenerative diseases, diabetes, cancer andstress. The prior teaching of the present specification concerning thecompounds of formula (I), including any preferred embodiment thereof, isvalid and applicable without restrictions to the compounds according toformula (I) and their salts for use in the prophylactic or therapeutictreatment and/or monitoring of neurodegenerative diseases, diabetes,cancer and stress.

Another aspect of the invention relates to a method for treating adisease that is caused, mediated and/or propagated by OGA activity,wherein an effective amount of at least one compound of formula (I)according to the invention and/or physiologically acceptable saltsthereof is administered to a mammal in need of such treatment. Anotheraspect of the invention relates to a method for treatingneurodegenerative diseases, diabetes, cancer and stress, preferably atauopathy, wherein an effective amount of at least one compound offormula (I) according to the invention and/or physiologically acceptablesalts thereof is administered to a mammal in need of such treatment. Thepreferred treatment is an oral administration. The prior teaching of theinvention and its embodiments is valid and applicable withoutrestrictions to the methods of treatment if expedient.

The neurodegenerative disease or condition is more preferably selectedfrom the group of one or more tauopathies and Alzheimer's disease,dementia, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateralsclerosis with cognitive impairment (ALSci), Argyrophilic graindementia, Bluit disease, Corticobasal degeneration (CBP), Dementiapugilistica, Dementia with Lewy Bodies, Diffuse neurofibrillary tangleswith calcification, Down's syndrome, Familial British dementia, FamilialDanish dementia, Frontotemporal dementia with parkinsonism linked tochromosome 17 (FTDP-17), Frontotemporal Lobe Degeneration (FTLD),Ganglioglioma, Gangliocytoma, Gerstmann-Straussler-Scheinker disease,Guadeloupean parkinsonism, Hallevorden-Spatz disease (neurodegenerationwith brain iron accumulation type 1), Lead encephalopathy,Lipofuscinosis, Meningioangiomatosis, Multiple system atrophy, Myotonicdystrophy, Niemann-Pick disease (type C), Pallido-ponto-nigraldegeneration, Parkinsonism-dementia complex of Guam, Pick's disease(PiD), Postencephalitic parkinsonism (PEP), Prion diseases (includingCreutzfeldt-Jakob Disease (GJD), Variant Creutzfeldt-Jakob Disease(vCJD), Fatal Familial Insomnia, Kuru, Progressive supercorticalgliosis, Progressive supranuclear palsy (PSP), Pure Autonomic Failure,Richardson's syndrome, Subacute sclerosing panencephalitis, Tangle-onlydementia, Tuberous Sclerosis, Huntington's disease and Parkinson'sdisease. Most preferred are one ore more tauopathies and Alzheimer'sdisease.

The invention also relates to the use of compounds according to formula(I) and/or physiologically acceptable salts thereof for the prophylacticor therapeutic treatment and/or monitoring of diseases that are caused,mediated and/or propagated by OGA activity. Furthermore, the inventionrelates to the use of compounds according to formula (I) and/orphysiologically acceptable salts thereof for the production of amedicament for the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byOGA activity. Compounds of formula (I) and/or a physiologicallyacceptable salt thereof can furthermore be employed as intermediate forthe preparation of further medicament active ingredients. The medicamentis preferably prepared in a non-chemical manner, e.g. by combining theactive ingredient with at least one solid, fluid and/or semi-fluidcarrier or excipient, and optionally in conjunction with a single ormore other active substances in an appropriate dosage form.

The compounds of formula (I) according to the invention can beadministered before or following an onset of disease once or severaltimes acting as therapy. The aforementioned compounds and medicalproducts of the inventive use are particularly used for the therapeutictreatment. A therapeutically relevant effect relieves to some extent oneor more symptoms of a disorder, or returns to normality, eitherpartially or completely, one or more physiological or biochemicalparameters associated with or causative of a disease or pathologicalcondition. Monitoring is considered as a kind of treatment provided thatthe compounds are administered in distinct intervals, e.g. in order tobooster the response and eradicate the pathogens and/or symptoms of thedisease completely. Either the identical compound or different compoundscan be applied. The medicament can also be used to reducing thelikelihood of developing a disorder or even prevent the initiation ofdisorders associated with OGA activity in advance or to treat thearising and continuing symptoms. The disorders as concerned by theinvention are preferably neurodegenerative diseases, diabetes, cancerand stress.

In the meaning of the invention, prophylactic treatment is advisable ifthe subject possesses any preconditions for the aforementionedphysiological or pathological conditions, such as a familialdisposition, a genetic defect, or a previously passed disease.

In the scope of the present invention, compounds of formula (I) areprovided for the first time. The low molecular weight compounds of theinvention are strong and selective glycosidase inhibitors with improvedpassive permeability. The compounds of formula (I) have been shown to becompetitive with PUGNAc, a known OGA inhibitor that binds in thesubstrate pocket. The endogenous substrate is an O-GlcNAcylated protein.O-GlcNAcylation of nuclear and cytoplasmic proteins is one of the mostcommon post-translational modifications in animals and plants. O-GlcNAccycling modulates a number of cellular processes, and evidence ismounting that dysregulation of O-GlcNAcylation plays a role in theetiology of several diseases, including tauopathies and Alzheimer'sdisease. O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) are the twoenzymes that regulate O-GlcNAc cycling. Emerging data suggest thatinhibitors that block OGA may help maintain healthy O-GlcNAc levels intauopathies and Alzheimer's disease patients and thereby inhibit theformation of neurofibrillary tangles. Hence, the current inventioncomprises the use of compounds of formula (I) in the regulation,modulation and/or inhibition of the glycosidase signal cascade, whichcan be advantageously applied as research tool, for diagnosis and/or intreatment of any disorders that are responsive to OGA signaling andinhibition.

The low molecular weight inhibitors can be applied either themselvesand/or in combination with physical measurements for diagnostics oftreatment effectiveness. Medicaments and pharmaceutical compositionscontaining said compounds and the use of said compounds to treatglycosidase-mediated conditions is a promising, novel approach for abroad spectrum of therapies causing a direct and immediate improvementin the state of health, whether in man and animal. The impact is ofspecial benefit to efficiently combat tauopathies and Alzheimer'sdisease, either alone or in combination with other neurodegenerativetreatments.

Due to the surprisingly appreciable inhibitory activity on OGA, alongwith passive permeability, the compounds of the invention can beadvantageously administered at lower doses compared to other less potentor selective inhibitors of prior art while still achieving equivalent oreven superior desired biological effects. In addition, such a dosereduction advantageously leads to less or even no medicinal adverseeffects.

The compounds of formula (I), their salts, isomers, tautomers,enantiomeric forms, diastereomers, racemates, derivatives, prodrugsand/or metabolites are characterized by a high specificity andstability, low manufacturing costs and convenient handling. Thesefeatures form the basis for a reproducible action, wherein the lack ofcross-reactivity is included, and for a reliable and safe interactionwith the target structure.

All the references cited herein are incorporated by reference in thedisclosure of the invention hereby.

The techniques that are essential according to the invention aredescribed in detail in the specification. Other techniques which are notdescribed in detail correspond to known standard methods that are wellknown to a person skilled in the art, or the techniques are described inmore detail in cited references, patent applications or standardliterature. Although methods and materials similar or equivalent tothose described herein can be used in the practice or testing of thepresent invention, suitable examples are described below. The followingexamples are provided by way of illustration and not by way oflimitation. Within the examples, standard reagents and buffers that arefree from contaminating activities (whenever practical) are used. Theexamples are particularly to be construed such that they are not limitedto the explicitly demonstrated combinations of features, but theexemplified features may be unrestrictedly combined again provided thatthe technical problem of the invention is solved. Similarly, thefeatures of any claim can be combined with the features of one or moreother claims.

EXPERIMENTAL PART

The compounds according to Formula (I) can be prepared from readilyavailable starting materials by several synthetic approaches, using bothsolution-phase and solid-phase chemistry protocols or mixed solution andsolid phase protocols. Examples of synthetic pathways are describedbelow in the examples. All reported yields are non optimized yields.Unless otherwise stated, compounds of Formula (I) and related formulaeobtained as a racemic mixture can be separated to provide anenantiomerically enriched mixture or a pure enantiomer.

The commercially available starting materials used in the followingexperimental description were purchased from Aldrich, Sigma, ACROS,ABCR, Combi-Blocks, Matrix, Apollo scientific, Alfa Aesar, etc. unlessotherwise reported.

The HPLC, MS and NMR data provided in the examples described below areobtained as followed:

¹H NMR analyses were carried out using BRUKER NMR, model AV-II andAV-III 400 MHz FT-NMR. Residual signal of deuterated solvent was used asinternal reference. Chemical shifts (δ) are reported in ppm in relativeto the residual solvent signal (δ=2.50 for ¹H NMR in DMSO-d₆, and 7.26in CDC₃). s (singlet), d (doublet), t (triplet), q (quadruplet), br(broad), quint (quintuplet).

The MS data provided in the examples described below were obtained asfollowed: Mass spectrum: LC/MS Agilent (ESI/APCI), Chemstration, 1200Series.

LCMS Methods:

Method A

Method: A—0.1% TFA in H₂O, B—0.1% TFA in ACN: Flow—2.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm+ve mode

Method B

Method: A—10 mM NH₄HCO₃ in H₂O, B—ACN: Flow—1.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm), +ve mode

Method C

Method: A—10 mM NH₄HCO₃ in H₂O, B—ACN: Flow—1.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm), −ve mode

HPLC analyses were obtained using Agilent 1200 Series instruments asfollowed using % with UV detection (maxplot).

Method A

Method: A—0.1% TFA in H₂O, B—0.1% TFA in ACN: Flow—2.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm).

Method B

Method: A—10 mM NH₄HCO₃ in H₂O, B—ACN: Flow—1.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm).

Method C

Method: Gradient from 70% H₂O (10 mM K₂HPO₄): 30% MeCN to 70% MeCN over15 minutes, Flow: 1 mL/min. Column: XTERRA RP18 (250×4.6) mm, 5 μm

Chiral HPLC

Method A

Mobile Phase: 0.1% DEA in n-HEXANE:IPA: 60:40; COLUMN: CHIRALPAK AD-H(250×4.6) mm, 5 μm, FLOW: 1.0 mL/min

Method B:

Mobile Phase: n-HEXANE:EtOH: 90:10: FLOW: 1.0 mL\min; COLUMN: CHIRALPAKIC (250×4.6) mm, 5 μm

Method C:

Mobile Phase: 0.1% TFA in n-HEXANE:IPA: 60:40; COLUMN: CHIRALcell OD-H(250×4.6) mm, 5 μm, FLOW: 1.0 mL/min

Method D:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 1.0 mL\min; COLUMN:Chiralcell OJ-H column (250×4.6) mm, 5 μm

Method E:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 1.0 mL\min; COLUMN:Chiralcell AY-H column (250×4.6) mm, 5 μm

Method F:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 70:30; FLOW: 1.0 mL\min; COLUMN:Chiralpak IA (250×4.6) mm, 5 μm

Method G:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 60:40; FLOW: 1.0 mL\min; COLUMN:Chiralcel OD-H (250×4.6) mm, 5 μm

Method H:

Mobile Phase: 0.1% DEA in n-Hexane:EtOH: 80:20; FLOW: 1.0 mL\min;COLUMN: CHIRALPAK IC (250×4.6) mm, 5 μm

General flash chromatography conditions used for the purification ofintermediates or compounds of Formula I: silica gel 230-400 mesh;gradients used as eluent: 10 to 80% EtOAc in Petroleum ether or 1 to 15%MeOH in DCM

MD Autoprep Conditions

The mass directed preparative HPLC purifications were performed with amass directed autopurification Fractionlynx from Waters.

Method A

0.1% HCOOH in H₂O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7μm

Method B

0.1% TFA in H₂O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7 μm

Method C

10 mM NH₄HCO₃ in H₂O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm),7 μm

Method D

10 mM NH₄OAC in H₂O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm),7 μm

Preparative HPLC Conditions

Method PA

0.1% TFA in H₂O, B-MeOH or ACN. Column: Sunfire C8 (19 mm×250 mm) 5 μmor Sunfire C18 (30 mm×250 mm) 10 μm.

Method PB

10 mM NH₄HCO₃ in H₂O, B-MeOH or ACN, Column: Sunfire C8 (19 mm×250 mm) 5μm or Sunfire C18 (30 mm×250 mm) 10 μm.

Chiral Preparative Method PC

Mobile phase: n-Hexane, IPA; Column: Chiral pak AD-H (20×250) mm, 5micron, Flow: 12 mL/min

Chiral Preparative Method PD:

Mobile phase: n-Hexane, IPA; Column: Chiral pak AD-H (20×250) mm, 5micron, Flow: 12 mL/min

Chiral Preparative Method PE:

Mobile phase: n-Hexane, IPA; Column: Chiralcell OD-H (20×250) mm, 5micron, Flow: 12 mL/min

Chiral Preparative Method PF:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 12.0 mL\min; COLUMN:Chiralcell OJ-H column (250×20) mm, 5 μm

Chiral Preparative Method PG:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 20.0 mL\min; COLUMN:Chiralcell AY-H column (250×30) mm, 5 μm

Chiral Preparative Method PH:

Mobile Phase: n-HEXANE: ETOH: 90:10: FLOW: 20.0 mL\min; COLUMN:CHIRALPAK IC (250×30) mm, 5 μm

Chiral Preparative Method PI:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 12.0 mL\min; COLUMN:Lux Cellulose C4 (250×21.2) mm, 5 μm

Chiral Preparative Method PJ:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 70:30; FLOW: 12.0 mL\min; COLUMN:Chiralpak IA (250×20) mm, 5 μm

Chiral Preparative Method PK:

Mobile Phase: 0.1% DEA In Hexane:EtOH: 50:50; FLOW: 10.0 mL/min; COLUMN:Chiralpac IC (250×21) mm, 5 μm

The SFC purifications were performed with a Prep SFC, THAR-SFC 80 andTHAR-SFC 200.

The microwave chemistry was performed on a single mode microwave reactorInitiator™ Sixty from Biotage.

General Procedure for Ester Reduction of Heterocycles: Procedure A

To a stirred solution of ester (1 equiv) in dry THF (20 to 35 mL),lithium triethylborohydride (1 M solution in THF, 1.7 equiv) was addedslowly at 0° C. The reaction mixture was stirred at room temperature for2 h. The completion of the reaction was monitored by TLC. Reactionmixture was cooled to 0° C. and quenched using 10% ammonium chloridesolution. Solvent was removed under vacuum and resulting residue waspurified by flash column chromatography to afford the desired product.

General Procedure for Chlorination of Hetrocyclic Alcohol: Procedure B

To a stirred solution of alcohol (1 equiv) in dry DCM (10 to 20 mL),thionyl chloride (1.7 to 3 equiv) was added slowly at 0° C. The reactionmixture was warmed to rt and was refluxed for 1 h. The reaction mixturewas concentrated under vacuum and the resulting residue was diluted withDCM (20 to 50 mL). The DCM layer was washed with water (5 to 10 mL),brine solution (5 to 10 mL), dried over anhydrous Na₂SO₄ andconcentrated under vacuum to give chloro compound.

General Procedure for Reductive Amination: Procedure C

To a solution of aldehyde (1 equiv) in dry THF (4 to 10 mL), amine (0.8to 1.1 equiv), acetic acid (7 equiv) was added at room temperature andstirred for 30 min. Then the reaction mixture was cooled to 0° C. andsodium triacetoxy borohydride (1.2 equiv) was added slowly. Theresulting reaction mixture was stirred at room temperature for 16 h. Thereaction mixture was concentrated, the crude product was diluted with(10 to 20 mL) EtOAc and the organic layer was washed with (10-20 mL) ofbrine. The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude products were purified by flashcolumn chromatography to afford the desired product.

General Procedure for N-Alkylation: Procedure D

To a stirred solution of amine (1 mmol/0.8 to 1 equiv) in dry DMF (5 to10 mL), chloro compound (1.0 to 1.2 equiv) and potassium carbonate (2equiv) were added at rt. The resulting mixture was heated at 90° C. for16 h. It was concentrated under vacuum and the resulting residue wasdiluted with DCM (20 to 50 mL). The DCM layer was washed with water (5to 10 mL), brine solution (5 to 10 mL), dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude products were purified by flashchromatography to afford the desired product.

General Procedure for N-Alkylation: Procedure E

To a stirred solution of amine (1 mmol/1 equiv) in acetonitrile (5 to 10mL), chloro compound (1.5 to 2 equiv), triethyl amine (2 equiv) wereadded at rt. The resulting mixture was stirred at rt to 60° C. for 16 h.It was diluted with water (15 mL) and extracted with EtOAc (2×20 mL).The organic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The resulting crude product was purified by flashchromatography to afford the desired product.

INTERMEDIATES SYNTHESIS Intermediate 15-(1-Chloroethyl)benzo[d][1,3]dioxole

Step 1: 1-(Benzo[d][1,3]dioxol-5-yl)ethan-1-ol

To a stirred solution of 3,4-methylenedioxy acetophenone (4.5 g, 27mmol, Alfa aesar) in dry MeOH (50 mL), NaBH₄ (1.08 g, 42 mmol, Lobachemie) was added slowly at 0° C. The reaction mixture was stirred atroom temperature for 1 h. Then the reaction mixture was concentratedunder vacuum and diluted with DCM. The DCM layer was washed with water,brine and dried over anhydrous Na₂SO₄. The solvent was removed underreduced pressure and resulting crude alcohol was used as such in thenext step. Yield: 90% (4.0 g, colorless liquid). ¹H NMR (400 MHz,CDCl₃): δ 6.89 (s, 1H), 6.89-6.75 (m, 2H), 5.95 (s, 2H), 4.81 (t, J=8.0Hz, 1H), 1.46 (d, J=8.0 Hz, 3H). LCMS: (Method B) 149.0 (Hydroxyelimination mass), Rt. 2.51 min, 98.6% (Max). HPLC: (Method A) Rt. 2.499min, 99.5% (Max).

Step 2: 5-(1-Chloroethyl)benzo[d][1,3]dioxole

The title compound was synthesized by following general procedure B. Itwas used for next step without further purification. Yield: 72% (1.2 g,colorless liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.06 (d, J=4.0 Hz, 1H),6.93 (d, J=8.0 Hz. 1H), 6.86 (d, J=8.0 Hz, 1H), 6.01 (s, 2H), 2.49 (q,J=8.0 Hz, 1H), 1.74 (d, J=8.0 Hz, 3H). LCMS: (Method B) 149.0(Cl-Elimination mass), Rt. 3.71 min, 80.15% (Max).

Intermediate 2 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazinehydrochloride

Step 1: tert-butyl4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine-1-carboxylate

The title compound was synthesized following general procedure D,starting with Intermediate 1 and N-boc piperazine. The crude product waspurified by flash chromatography, affording the title compound (yellowsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.85-6.82 (m, 2H), 6.74-6.71 (m,1H), 5.98 (m, 2H), 3.37-3.36 (m, 1H), 3.27 (br. s, 4H), 2.28-2.21 (m,4H), 1.37 (s, 9H), 1.25 (d, 3H, J=6.8 Hz). LCMS: (Method A) 335.2 (M+H),Rt. 3.10 min, 93.15% (Max). HPLC: (Method A) Rt. 3.12 min, 95.01% (Max).

Step 2: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazine hydrochloride

To a stirred solution of tert-butyl4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine-1-carboxylate (1.8 g,5.38 mmol) in dry dioxane (10 mL), HCl in dioxane (10 mL, 4 M,Spectrochem) was added at rt and stirred for 2 h at same temperature.The reaction mixture was concentrated under vacuum and the resultingcrude product was washed with diethyl ether to afford the title productas hydrochloride salt. Yield: 82% (1.2 g, off white solid). ¹H NMR (400MHz, DMSO-d₆): δ 12.29 (s, 1H), 7.34 (s, 1H), 7.08 (d, 1H, J=7.7 Hz),7.00 (d, 1H, J=7.9 Hz), 6.07 (s, 2H), 4.54 (br. s, 1H), 3.81 (br. s,1H), 3.49-3.42 (m, 3H), 3.33 (br. s, 2H), 3.12 (br. s, 1H), 2.99 (br. s,1H), 1.67 (d, 3H, J=5.7 Hz). LCMS: (Method A) 235.0 (M+H), Rt. 1.65 min,98.08% (Max). HPLC: (Method A) Rt. 1.56 min, 99.86% (Max).

Intermediate 3 6-(1-chloroethyl)-2,3-dihydrobenzo[b][1,4]dioxine

Step 1: 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-ol

The title compound was synthesized with same protocol as described forIntermediate 1, Step 1, using1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (2.0 g, 11.2 mmol)and NaBH₄ (0.49 g, 13 mmol). The resulting crude alcohol was used assuch in the next step. Yield: 99% (2.0 g, colorless liquid). ¹H NMR (400MHz, DMSO-d₆): δ 6.80 (s, 1H), 6.79-6.76 (m, 2H), 4.59 (q, J=5.6 Hz,1H), 4.20 (s, 4H), 1.26 (d, J=5.6 Hz, 3H). LCMS: (Method B) 163.0(Hydroxy elimination mass), Rt. 2.51 min, 99.4% (Max).

Step 2: 6-(1-chloroethyl)-2,3-dihydrobenzo[b][1,4]dioxine

The title compound was synthesized according to the general procedure B.It was used in the next step without further purification. Yield: 90%(2.2 g, brown liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.97 (s, 1H),6.96-6.92 (m, 1H), 6.84-6.82 (m, 1H), 5.26 (t, J=6.7 Hz, 1H), 4.23 (s,4H), 1.75 (d, J=6.7 Hz, 3H). LCMS: (Method A) 163.0 (Cl-Eliminationmass), Rt. 3.66 min, 95.3% (Max).

Intermediate 41-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazine hydrochloride

Step 1: t-Butyl4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazine-1-carboxylate

The title compound was synthesized according to the general procedure D,starting with Intermediate 3 (5 g, 25.2 mmol) and N-boc piperazine (3.96g, 21.2 mmol). The crude product was purified by flash chromatography,affording the title compound. Yield: 52% (4.6 g, brown liquid). ¹H NMR(400 MHz, DMSO-d₆): δ 6.80-6.71 (m, 3H), 4.21 (s, 5H), 3.34-3.26 (m,4H), 2.27-2.24 (m, 4H), 1.37 (s, 9H), 1.23 (d, J=6.7 Hz, 3H). LCMS:(Method A) 349.2 (M+H), Rt. 3.19 min, 80.9% (Max).

Step 2: 1-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazinehydrochloride

To a stirred solution of tert-butyl4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazine-1-carboxylate(4.6 g, 13.20 mmol) in dry dioxane (5.0 mL), HCl in dioxane (10.0 mL, 4M, Spectrochem) was added at 0° C. The reaction mixture was stirred atrt for 2 h. The completion of the reaction was monitored by TLC. Thereaction mixture was concentrated. Diethyl ether was added and wasevaporated again, affording the title compound. Yield: 89% (3.8 g, offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.08 (br. s, 1H), 9.48-9.18(m, 2H), 7.18 (s, 1H), 7.03 (s, 1H), 6.92 (d, J=10.6 Hz, 1H), 4.49 (s,1H), 4.24 (s, 4H), 3.41-3.15 (m, 4H), 2.91-2.71 (m, 4H), 1.64 (s, 3H).LCMS: (Method A) 249.2 (M+H), Rt. 1.64 min, 92.6% (Max).

Intermediate 5 5-(1-chloroethyl)-2,3-dihydrobenzofuran

Step 1: 1-(2,3-dihydrobenzofuran-5-yl)ethan-1-ol

To a stirred solution of 1-(2,3-dihydrobenzofuran-5-yl)ethan-1-one (2.0g, 13.0 mmol) in dry MeOH (20 mL), NaBH₄ (0.68 g, 26.0 mmol, Lobachemie) was added slowly at 0° C. The reaction mixture was stirred at rtfor 1 h. It was then concentrated under vacuum and the resulting crudeproduct was dissolved in DCM (50 mL), washed with water, brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was used in the next step without further purification. Yield:91% (1.83 g).

Step 2: 5-(1-chloroethyl)-2,3-dihydrobenzofuran

The title compound was synthesized following the general procedure B.The reaction mixture was concentrated under vacuum and the resultingcrude mixture was used without further purification.

Yield: 72% (0.6 g, colorless liquid). LCMS: (Method B) 149.0 (chloroelimination mass), Rt. 3.705 min, 80.15% (Max).

Intermediate 6 6-(1-chloroethyl)quinoxaline

Step 1: 1-(quinoxalin-6-yl)ethan-1-one

6-Bromo quinoxaline (2.0 g, 9.5 mmol) in toluene (20 mL) was degassedfor 30 min. To this solution, 1-ethoxy vinyl tributyltin (3.8 g, 10.5mmol) and bis(triphenylphosphine)palladium dichloride (0.67 g, 0.95mmol) were added at rt and stirred for 16 hours at 90° C. The reactionmixture was cooled to rt and filtered through celite. After evaporationof the solvent, 6 N HCl solution in water (20 mL) was added and themixture was stirred for 1 hour at rt. It was concentrated andneutralized with sat. NaHCO₃. The desired product was extracted with DCM(100 mL), dried over Na₂SO₄ and concentrated. The crude product waspurified by flash column chromatography to afford the title compound(brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.06-9.04 (m, 2H), 8.70 (d,J=2.4 Hz, 1H), 8.28 (t, J=2.8 Hz, 1H), 8.16 (d, J=11.6 Hz, 1H), 2.97 (s,3H). LCMS: (Method A) 173 (M+H), Rt. 2.25 min, 99.06% (Max).

Step 2: 1-(quinoxalin-6-yl)ethan-1-ol

To a stirred solution of 1-(quinoxalin-6-yl)ethan-1-one (0.8 g, 4.65mmol) in dry MeOH (20 mL), sodium borohydride (0.36 g, 9.3 mmol) wasadded portion wise at 0° C. and the resulting mixture was stirred for 1h. It was then concentrated, diluted with DCM (80 mL), washed with water(20 mL), dried over Na₂SO₄ and concentrated. The crude product was takenfor next step without further purification. Yield: 75% (600 mg, darkbrown liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.91-8.89 (m, 2H), 8.03 (t,J=11.6 Hz, 2H), 7.87-7.86 (m, 1H), 5.49 (d, J=5.9 Hz, 1H), 4.97 (t,J=6.2 Hz, 1H), 1.42 (d, J=8.6 Hz, 3H). LCMS: (Method A) 175.0 (M+H), Rt.1.89 min, 95.0% (Max).

Step 3: 6-(1-chloroethyl)quinoxaline

To a stirred solution of 1-(quinoxalin-6-yl)ethan-1-ol (0.6 g, 3.46mmol) in dry DCM (10 mL), thionyl chloride (0.5 mL, 6.93 mmol) was addeddropwise at 0° C. and stirred at rt for 1 hour. The reaction mixture wasevaporated to dryness and was used without further purification. Yield:97% (650 mg, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.74 (s,2H), 7.93 (s, 1H), 7.70-7.68 (m, 2H), 4.46-4.23 (m, 1H), 1.87 (s, 3H).LCMS: (Method A) 193 (M+H), Rt. 3.41 min, 71.4% (Max).

Intermediate 7 N-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamidehydrochloride

Step 1: tert-Butyl4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of 2-amino 5-bromo-1,3,4-thiadiazole (10.0 g, 55.5mmol) in dry DMF (100 mL), K₂CO₃ (15.3 g, 111.1 mmol) and 1-bocpiperazine (12.4 g, 66.65 mmol) were added at 0° C. The reaction mixturewas stirred overnight at 80° C. The reaction mixture was concentratedunder vacuum. To the resulting crude solids, DCM (200 mL) was added. TheDCM layer was washed with water (100 mL), brine (100 mL) and, dried overanhydrous Na₂SO₄ and concentrated. The crude product was purified bysilica gel column chromatography to afford the title compound. Yield:76% (12 g, pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.51 (s, 2H),3.39 (d, J=6.9 Hz, 4H), 3.19 (d, J=7.7 Hz, 4H), 1.39 (s, 9H). LCMS:(Method A) 286.1 (M+H), Rt. 2.71 min, 97.6% (Max).

Step 2: tert-Butyl4-(5-acetamido-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (12.0 g, 42.09mmol) in pyridine (120 mL), acetic anhydride (5.1 g, 50.5 mmol) wasadded at 0° C. The reaction mixture was stirred overnight at 50° C. Thereaction mixture was concentrated under vacuum and triturated withdiethyl ether (100 mL). The solid obtained was filtered, washed withdiethyl ether (20 mL), dried and taken for next step without any furtherpurification. Yield: 87% (12 g, off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 12.07 (br .s, 1H), 3.45-3.34 (m, 8H), 2.11 (s, 3H), 1.42 (s,9H). LCMS: (Method A) 328.0 (M+H), Rt. 3.11 min, 86.3% (Max).

Step 3: N-(5-(Piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamidehydrochloride

To a stirred solution of tert-butyl4-(5-acetamido-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (12.0 g)in dry dioxane (100 mL), HCl in dioxane (100 mL, 4 N) was added and thereaction mixture was stirred at rt for 3 h. The reaction mixture wasconcentrated under vacuum and the resulting crude product was suspendeddiethyl ether (50 mL). The title compound was obtained after evaporationof the solvent. Yield: 93% (9 g, white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 12.07 (br. s, 1H), 3.67 (s, 4H), 3.21 (s, 4H), 2.13 (s, 3H).LCMS: (Method A) 228.0 (M+H), Rt. 0.71 min, 85.3% (Max).

Intermediate 8 Ethyl 2-(piperazin-1-yl)thiazole-5-carboxylatehydrochloride

Step 1: Ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-5-carboxylate

To a stirred solution of ethyl 2-bromothiazole-5-carboxylate (4.0 g,17.0 mmol) in dry DMF (40 mL), triethylamine (7.3 mL, 51.0 mmol,Spectrochem), followed by N-Boc piperazine (3.6 g, 19.0 mmol,GLRscientific) were added. The resulting mixture was heated at 90° C.for 12 h. It was then concentrated, diluted with DCM (200 mL), washedwith water (100 mL) and dried over Na₂SO₄. After evaporation of thesolvents, the crude product was purified by flash chromatography (3%methanol in DCM) to afford the title compound. Yield: 77% (4.5 g, whitesolid). LCMS: (Method A) 342.0 (M+H), Rt. 4.42 min, 99.5% (Max). ¹H NMR(400 MHz, CDCl₃): δ 7.88 (s, 1H), 4.30 (q, J=7.2 Hz, 2H), 3.57 (s, 8H),1.49 (s, 9H), 1.35 (t, J=7.2 Hz, 3H).

Step 2: Ethyl 2-(piperazin-1-yl)thiazole-5-carboxylate hydrochloride

To a stirred solution of ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-5-carboxylate (4.5 g,13.0 mmol) in dry dioxane (20 mL), HCl in dioxane (4 N, 50 mL) was addedat 0° C. and the reaction mixture was stirred at rt for 2 h. Thereaction mixture was concentrated and the resulting solid was washedwith diethyl ether and dried under vacuum. Yield: 90% (5.4 g, off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.32 (s, 2H), 7.88 (s, 1H), 4.21(q, J=9.4 Hz, 2H), 3.96-3.73 (m, 4H), 3.55-2.41 (m, 4H), 1.24 (t, J=7.0Hz, 3H). LCMS: (Method B) 242.0 (M+H), Rt. 2.11 min, 99.8% (Max).

Intermediate 9 7-(1-chloroethyl)quinoline

Step 1: 1-(quinolin-7-yl)ethan-1-one

The title compound was synthesized according to the protocol describedfor the synthesis of Intermediate 6, step 1, using 7-bromo quinoline (2g, 9.56 mmol, Harvechem) as starting material. The crude product waspurified by flash chromatography to afford the title compound (brownsolid). ¹H NMR (300 MHz, DMSO-d₆): δ 9.02 (d, J=3.2 Hz, 1H), 8.63 (s,1H), 8.46-8.10 (m, 1H), 8.08-8.03 (m, 2H), 7.68-7.50 (m, 1H), 2.68 (s,3H). LCMS: (Method A) 172.0 (M+H), Rt. 1.49 min, 84.1% (Max).

Step 2: 1-(quinolin-7-yl)ethan-1-ol

The title compound was synthesized according to the protocol describedfor the synthesis of Intermediate 6, step 2, using1-(quinolin-7-yl)ethan-1-one as starting material. The crude product wastaken for next step without further purification (brown solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.86-8.85 (m, 1H), 8.31 (d, J=8.1 Hz, 1H), 7.92(t, J=8.5 Hz, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.47 (dd, J=4.2, 8.2 Hz, 1H),5.39 (d, J=4.2 Hz, 1H), 4.90-4.96 (m, 1H), 1.41 (d, J=6.4 Hz, 3H). LCMS:(Method A) 174.0 (M+H), Rt. 1.34 min, 99.2% (Max).

Step 3: 7-(1-chloroethyl)quinoline

The title compound was synthesized according to the protocol describedfor the synthesis of Intermediate 6, step 3, using1-(quinolin-7-yl)ethan-1-ol as starting material. The crude product wastaken for next step without further purification. Yield: 96% (260 mg,grey solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.19 (d, J=3.5 Hz, 1H), 8.88(d, J=7.6 Hz, 1H), 8.27 (d, J=6.6 Hz, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.93(dt, J=6.0, Hz, 2H), 5.71-5.68 (m, 1H), 1.91 (d, J=6.7 Hz, 3H). LCMS:(Method A) 192.0 (M+H), Rt. 2.27 min, 98.7% (Max).

Intermediate 10 N-(2-(piperazin-1-yl)pyrimidin-5-yl)acetamide,hydrochloride

Step 1: Tert-butyl 4-(5-nitropyrimidin-2-yl)piperazine-1-carboxylate

To a stirred solution of 2-chloro-5-nitro-pyrimidine (2.2 g, 13.7 mmol)in dry DMF (25 mL), triethylamine (5.7 mL, 41.3 mmol, Spectrochem)followed by N-Boc piperazine (2.8 g, 15.7 mmol) were added and theresulting mixture was heated at 90° C. for 12 h. It was concentrated andthe residue was diluted with DCM (50 mL), washed with water (15 mL) anddried over Na₂SO₄. After evaporation of the solvents, the crude productwas washed with ACN with 5% methanol to afford the title compound (brownsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.12 (s, 2H), 3.92-3.88 (m, 4H),3.45-3.42 (m, 4H), 1.4 (s, 9H). LCMS: (Method A) 254.0 (M-(t-butyl)+H),Rt. 4.43 min, 98.03% (Max).

Step 2: Tert-butyl 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-(5-nitropyrimidin-2-yl)piperazine-1-carboxylate (2.1 g, 6.79 mmol) inmethanol (25 mL), Pd/C (10%, 0.210 g, Aldrich) was added and thereaction mixture was stirred under H₂ atmosphere for 3 h. The reactioncompletion was monitored by TLC. The reaction mixture was filteredthrough celite and evaporated under vacuum. The crude product was usedwithout further purification. Yield: 95% (1.8 g, pale brown solid). ¹HNMR (400 MHz, DMSO-d₆): δ 7.88 (s, 2H), 4.62 (s, 2H), 3.48-3.45 (m, 4H),3.35-3.28 (m, 4H), 1.33 (s, 9H). LCMS: (Method A) 280 (M+H), Rt. 2.66min, 98.82% (Max).

Step 3: Tert-butyl 4-(5-acetamidopyrimidin-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate (1.8 g, 6.44 mmol) indry DCM (18 mL), pyridine (0.7 mL, 9.67 mmol, spectrochem), aceticanhydride (0.9 mL, 9.67 mmol, spectrochem) and dimethyl aminopyridine(0.036 g, 2%, spectrochem) were added. The resulting mixture was stirredat rt for 12 h. The reaction mixture was concentrated under reducedpressure and the resulting solid was suspended in HCl (1.5 N in water,15 mL). The solid was filtered and washed with water (200 mL) to affordthe title compound. Yield: 87% (1.8 g, off white solid). ¹H NMR (400MHz, DMSO-d₆): δ 9.85 (s, 1H), 8.51 (s, 2H), 3.66-3.61 (m, 4H),3.33-3.31 (m, 4H), 2.00 (s, 3H), 1.41 (s, 9H). LCMS: (Method A) 322(M+H), Rt. 3.1 min, 98.4% (Max).

Step 4: N-(2-(piperazin-1-yl)pyrimidin-5-yl)acetamide

To a stirred solution of tert-butyl4-(5-acetamidopyrimidin-2-yl)piperazine-1-carboxylate (1.8 g, 5.6 mmol)in dry dioxane (5 mL) at 0° C., a solution of HCl in dioxane (4 N, 15mL) was added and the reaction mixture was stirred 3 h at rt. It wasconcentrated and the resulting product washed with diethyl ether,affording the title compound. Yield: 83% (1.8 g, off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 10.9 (s, 1H), 9.92 (s, 1H), 8.86 (s, 2H),3.22-3.17 (m, 4H), 3.02-2.78 (m, 4H), 2.06 (s, 3H). LCMS: (Method B)222.0 (M+H), Rt. 2.36 min, 95.34% (Max)

Intermediate 11 6-(1-(piperazin-1-yl)ethyl)quinoxaline hydrochloride

Step 1: tert-butyl 4-(1-(quinoxalin-6-yl)ethyl)piperazine-1-carboxylate

To a stirred solution of 1-boc piperazine (3.8 g, 20.83 mmol) in dry DMF(40 mL), TEA (8.7 mL, 62.4 mmol) and Intermediate 6 (4 g, 20.83 mmol)were added at rt and the reaction mixture was stirred overnight at 90°C. The reaction mixture was cooled to rt and concentrated under vacuum.To this crude mixture, water (50 mL) was added and the product wasextracted with DCM (150 mL). Organic layer was dried over anhydrousNa₂SO₄ and concentrated to get the crude product. The crude product waspurified by flash column chromatography to afford the title compound(brown solid). LCMS: (Method A) 343.2 (M+H), Rt. 2.59 min, 75.3% (Max).

Step 2: 6-(1-(piperazin-1-yl)ethyl) quinoxaline hydrochloride

To a solution of tert-butyl 4-(1-(quinoxalin-6-yl)ethyl)piperazine-1-carboxylate (3.5 g, 10.23 mmol) in methanol (5 mL), dioxaneHCl (35 mL, 10 V) was added at rt and the reaction mixture was stirredat for 2 h. The reaction mixture was concentrated under reduced pressureand then triturated with diethyl ether (15 mL) to afford the titlecompound. Yield: 87% (2.1 g, brown solid). ¹H NMR (400 MHz, DMSO-d₆):8.94 (d, J=6.0 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.88 (d,J=8.8 Hz, 1H), 3.85 (d, J=6.8 Hz, 1H), 3.54 (t, J=5.2 Hz, 2H), 3.16 (d,J=3.6 Hz, 2H), 3.06-2.96 (m, 1H), 2.92-3.02 (m, 1H), 2.67 (s, 2H),2.55-2.58 (m, 2H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 243.3 (M+H),Rt. 1.36 min, 95.02% (Max).

Intermediate 12 4-chloro-7-(1-chloroethyl)quinoline

Step 1—1-(4-chloroquinolin-7-yl)ethan-1-one

7-Bromo-4-chloroquinoline (1 g, 4.12 mmol, combiblock) in toluene (5 mL)was degassed for 30 min. To this solution, 1-ethoxy vinyl tributyltin(1.6 mL, 4.53 mmol) and bis(triphenylphosphine)palladium dichloride(3.38 g, 4.76 mmol) were added at rt and stirred for 12 hours at 90° C.The reaction mixture was cooled to rt and filtered through celite. Theresulting crude product was suspended in 6 N HCl in water (10 mL) andstirred for 1 hour at rt. The mixture was concentrated and neutralizedwith saturated aqueous solution of NaHCO₃. The desired product wasextracted with DCM (50 mL), dried over Na₂SO₄ and concentrated. Thecrude product was purified by flash column chromatography to afford thetitle compound (pale yellow solid). ¹H NMR (400 MHz, DMSO-d₆): 8.98 (d,J=4.6 Hz, 2H), 8.72 (s, 1H), 8.33 (d, J=8.7 Hz, 1H), 8.21 (d, J=8.7 Hz,1H), 7.92 (d, J=4.6 Hz, 1H), 2.78 (s, 3H). LCMS: (Method A) 206.0 (M+H),Rt. 2.98 min, 96.8% (Max).

Step-2—1-(4-chloroquinolin-7-yl)ethan-1-ol

To a stirred solution of 1-(4-chloroquinolin-7-yl)ethan-1-one (0.39 g,1.92 mmol) in dry MeOH (5 mL), sodium borohydride (0.108 g, 2.88 mmol)was added portion wise at 0° C. and stirred for 1 h. The reactionmixture was concentrated, diluted with DCM (50 mL) and washed with water(20 mL). The organic layer was dried over Na₂SO₄ and concentrated. Thecrude product was taken for next step without further purification.Yield: 95% (0.38 g, colourless liquid). ¹H NMR (400 MHz, DMSO-d₆): δ8.81 (d, J=6.3 Hz, 1H), 8.15-8.30 (m, 1H), 8.02 (s, 1H), 7.69-7.78 (m,2H), 5.47 (d, J=5.8 Hz, 1H), 4.92-5.00 (m, 1H), 1.42 (t, J=8.6 Hz, 3H).

Step-3: 4-chloro-7-(1-chloroethyl)quinoline

To a stirred solution of 1-(4-chloroquinolin-7-yl)ethan-1-ol (0.38 g,1.82 mmol) in dry DCM (10 mL), thionyl chloride (0.4 mL, 5.4 mmol) wasadded dropwise at 0° C. and stirred at rt for 1 hour. The reactionmixture was concentrated and dried under vacuum and used as such fornext step without any further purification. Yield: 97% (0.4 g,colourless liquid). ¹H NMR (400 MHz, DMSO-d₆): 8.89 (d, J=6.3 Hz, 1H),8.21-8.26 (m, 2H), 7.87-7.92 (m, 2H), 5.63 (q, J=8.8 Hz, 1H), 1.91 (s,3H). LCMS: (Method A) 226.0 (M+H), Rt. 3.54 min, 94.58% (Max).

Intermediate 13 5-(1-chloroethyl)benzo[c][1,2,5]oxadiazole

Step 1: 1-(benzo[c][1,2,5]oxadiazol-5-yl)ethan-1-one

A solution of 5-bromobenzo[c][1,2,5]oxadiazole (3 g, 15.0 mmol,Combiblocks) in toluene (10 mL) was degassed for 30 min. 1-Ethoxy vinyltributyltin (6.01 mL, 16.5 mole, Frontier Scientific) andbis(triphenylphosphine)palladium(II) dichloride (1.16 g, 1.65 mmol) wereadded at rt and the resulting mixture was stirred at 90° C. overnight.It was cooled to rt and filtered through celite. HCl aqueous solution(20 mL, 6N) was added and the mixture was stirred for 1 hour at rt. Itwas concentrated and neutralized with sat. NaHCO₃ solution (25 mL). Theproduct was extracted with DCM (100 mL), dried over Na₂SO₄ andconcentrated. The crude product was purified by flash columnchromatography to afford the title compound. Yield: 60% (1.5 g, paleyellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.90 (s, 1H), 8.14 (d, J=9.6Hz, 1H), 7.98-7.39 (m, 1H), 2.72 (s, 3H). LCMS: (Method B) 162.0 (M+H),Rt. 4.6 min, 98.01% (Max).

Step 2: 1-(benzo[c][1,2,5]oxadiazol-5-yl)ethan-1-ol

To a stirred solution of 1-(benzo[c][1,2,5]oxadiazol-5-yl)ethan-1-one(1.4 g, 8.53 mmol) in dry MeOH (20 mL), sodium borohydride (0.48 g, 12.7mmol, spectrochem) was added portion wise at 0° C. and stirred for 1 h.The reaction mixture was concentrated, diluted with DCM (60 mL) andwashed with water (10 mL). The organic layer was dried over Na₂SO₄ andconcentrated. The crude product was taken for next step without anyfurther purification. Yield: 98% (1.3 g, pale yellow solid). ¹H NMR (400MHz, DMSO-d₆): δ 6.85-6.82 (m, 2H), 6.71 (s, 1H), 4.36-4.30 (m, 1H),1.43 (d, J=6.4 Hz, 3H).

Step 3: 5-(1-chloroethyl)benzo[c][1,2,5]oxadiazole

To a stirred solution of 1-(benzo[c][1,2,5]oxadiazol-5-yl)ethan-1-ol (1g, 6.09 mmol) in dry DCM (10 mL), thionyl chloride (1.3 mL, 1.82 mmol,spectrochem) was added dropwise at 0° C. and stirred at rt for 1 hour.The reaction mixture was concentrated and used for next step without anyfurther purification. Yield: 91% (1.01 g, brown liquid). ¹H NMR (400MHz, DMSO-d₆): δ 7.77-7.75 (m, 1H), 7.64 (s, 1H), 7.24-7.19 (m, 1H),4.86-4.82 (m, 1H), 1.87 (d, J=6.7 Hz, 3H).

Intermediate 14 7-(1-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepine

Step 1: 1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)ethan-1-one

The title compound was synthesized following the same protocol asIntermediate 13, Step 1, using7-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepine (3 g, 13.0 mmol, Alfaaesar) as starting material. The crude product was purified by flashcolumn chromatography to afford the title compound. Yield: 50% (1.25 g,yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.57-7.52 (m, 2H), 7.05 (d,J=8.3 Hz, 1H), 4.25-4.18 (m, 4H), 2.16 (t, J=5.7 Hz, 2H), 1.73 (s, 3H).LCMS: (Method A) 193.0 (M+H), Rt. 3.2 min, 91.5% (Max).

Step 2: 1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl) ethan-1-ol

The title compound was synthesized following the same protocol asIntermediate 13, Step 2, using1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)ethan-1-one (1.21 g, 6.2mmol) as starting material. The crude product was taken for next stepwithout any further purification. Yield: 94% (1.1 g, Brown liquid). ¹HNMR (400 MHz, DMSO-d₆): δ 7.57-7.52 (m, 2H), 7.03 (d, J=8.1 Hz, 1H),5.65 (s, 1H), 5.28-5.23 (m, 1H), 4.13-4.10 (m, 4H), 2.14 (t, J=11.2 Hz,2H), 1.71 (d, J=6.7 Hz, 3H).

Step 3: 7-(1-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepine

The title compound was synthesized following the same protocol asIntermediate 13, Step 3, using1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)ethan-1-ol (1.15 g, 5.92mmol) as starting material. The crude product was used without anyfurther purification. Yield: 90% (1.0 g, brown liquid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.06-7.02 (m, 2H), 6.93 (d, J=8.1 Hz, 1H), 5.28-5.23 (m,1H), 4.13-4.10 (m, 4H), 2.14 (t, J=11.2 Hz, 2H), 1.73 (d, J=6.7 Hz, 3H).

Intermediate 15 8-(1-chloroethyl)quinolone

Step 1: 1-(quinolin-8-yl) ethan-1-one

A solution of 8-bromo quinoline (3 g, 14.4 mmol, Combiblock) in toluene(10 mL) was degassed for 30 min. To this solution, 1-ethoxy vinyltributyltin (5.72 mL, 15.8 mmol, Frontier Scientific) andbis(triphenylphosphine)palladium(II) dichloride (1.01 g, 1.44 mmol) wereadded at rt and stirred overnight at 90° C. The reaction mixture wascooled to rt and filtered through celite. HCl aqueous solution (20 mL, 6N) was added and the mixture was stirred for 1 hour at rt. It wasconcentrated and neutralized with saturated NaHCO₃ solution (25 mL). Thedesired product was extracted with DCM (100 mL), dried over anhydrousNa₂SO₄ and concentrated. The crude product was purified by flash columnchromatography to afford the title compound. Yield: 60% (1.5 g, brownliquid). ¹H NMR (300 MHz, DMSO-d₆): δ 9.01-8.99 (m, 1H), 8.46 (d, J=8.3Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.86 (d, J=7.1 Hz, 1H), 7.70-7.62 (m,2H), 2.82 (s, 3H). LCMS: (Method A) 172.0 (M+H), Rt. 0.82 min, 98.9%(Max).

Step 2: 1-(quinolin-8-yl) ethan-1-ol

To a stirred solution of 1-(quinolin-8-yl) ethan-1-one (1.5 g, 8.72mmol) in dry MeOH (20 mL), sodium borohydride (0.49 g, 13.0 mmol,Spectrochem) was added portion wise at 0° C. and the resulting mixturewas stirred for 1 h. It was concentrated, diluted with DCM (60 mL),washed with water (10 mL) and dried over Na₂SO₄. After evaporation ofthe solvents, the crude product was taken for next step without anyfurther purification. Yield: 79% (1.2 g, brown liquid). ¹H NMR (400 MHz,DMSO-d₆): δ 9.02-8.95 (m, 1H), 8.49 (d, J=8.1 Hz, 1H), 7.90 (t, J=8.5Hz, 2H), 7.75 (d, J=8.4 Hz, 1H), 7.63-7.60 (m, 1H), 5.17 (d, J=4.2 Hz,1H), 4.90-4.95 (m, 1H), 1.41 (d, J=6.4 Hz, 3H). LCMS: (Method A) 174.0(M+H), Rt. 1.31 min, 95.4% (Max).

Step 3: 8-(1-chloroethyl)quinoline

To a stirred solution of 1-(quinolin-8-yl) ethan-1-ol (0.30 g, 1.72mmol) in dry DCM (10 mL), thionyl chloride (0.4 mL, 2.89 mmol,spectrochem) was added dropwise at 0° C. and the resulting mixture wasstirred at rt for 1 hour. It was concentrated and the resulting productwas used in the next step without any further purification. Yield: 96%(0.28 g, grey liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.02 (d, J=1.7 Hz,1H), 8.50 (d, J=4.1 Hz, 1H), 8.08-8.02 (m, 2H), 7.73-7.64 (m, 2H), 6.64(t, J=8.0 Hz, 1H), 1.96 (d, J=6.7 Hz, 3H). LCMS: (Method A) 192.0 (M+H),Rt 2.81 min, 95.7% (Max).

Intermediate 16 (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazinehydrochloride

Step 1:(R)-N-(1-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide

To a mixture of 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-one (105.7 g, 644.6mmol), (R)-(+)-2-methyl-2-propanesulfinamide (85.79 g, 709 mmol) in THF(1.0 L), titanium(IV) ethoxide (294.06 g, 1289.2 mmol) was added at rtover 30 min and refluxed for 35 h. The reaction was monitored by HPLC.The reaction mixture was cooled to rt and slowly quenched with water(500 mL). The precipitate observed was filtered through celite bed (100g) and washed with EtOAc (2.0 L). The organic layer was washed withwater (500 mL), brine solution (300 mL) and dried over Na₂SO₄. (100 g)and evaporated under vacuum at 50° C. The resulting crude product wascodistilled with toluene (2×500 mL) and used as such for next stepwithout any further purification (164 g, brown liquid). LCMS: (Method A)268.0 (M+H), Rt. 3.87 min, 83.05% (Max). HPLC: (Method A) Rt. 3.81 min,57.62% (Max).

Step 2:(R)-N-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpropane-2-sulfinamide

To a stirred solution of(R)-N-(1-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide(96 g, 359 mmol) in THF (960 mL), L-Selectride (539 mL, 539 mmol, 1 Msolution in THF) was added under nitrogen atmosphere at −50° C. over 30min and stirred for 1 h. The completion of the reaction was confirmed byTLC. The reaction mixture was quenched with methanol (150 mL), water(750 mL) and stirred overnight at rt. The aqueous layer was extractedwith EtOAc (2×300 mL). The combined organic layer was washed with sat.NH₄Cl (2×250 mL), brine (250 mL), dried over Na₂SO₄ and evaporated undervacuum at 50° C. The resulting crude product (as light brown thick oil)was diluted with pet ether (250 mL) and stirred at −20° C. for 30 min.The resulting precipitate was filtered and washed with pet ether (2×100mL). It was dried under vacuum to give the title compound. Yield: 70.2%(68 g, Off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.89 (s, 1H),6.83-6.77 (m, 2H), 5.99-5.95 (m, 2H), 5.25 (d, J=5.2 Hz, 1H), 4.30 (q,J=6.0 Hz, 1H), 1.39 (d, J=1.6 Hz, 3H), 1.11-1.06 (m, 9H). LCMS: (MethodA) 270.0 (M+H), Rt. 3.66 min, 99.65% (Max). HPLC: (Method A) Rt. 3.62min, 99.69% (Max). Chiral HPLC: (Method C) Rt. 9.71 min, 100%.

Step 3: (S)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine

To a stirred solution of(R_(S))—N-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpropane-2-sulfinamide(68 g, 252 mmol) in MeOH (680 mL), thionyl chloride (74.3 g, 630 mmol)was added at 0° C. over 15 min and the resulting mixture was stirred atrt for 1 h. The completion of the reaction was confirmed by TLC. Thereaction mixture was concentrated under vacuum at 50° C. The resultingresidue was suspended in EtOAc (300 mL), filtered and washed with EtOAc(150 mL). The product was basified with 30% aqueous ammonia solution(300 mL) and extracted with EtOAc (2×250 mL). The combined organic layerwas washed with brine solution (1×150 mL) and dried over Na₂SO₄. Thesolvent was evaporated at under vacuum to give the title compound.Yield: 92.84% (38.3 g, brown liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.95(s, 1H), 6.81-6.77 (m, 2H), 5.95 (s, 2H), 3.90 (q, J=6.56 Hz, 1H), 1.85(s, 2H), 1.19 (m, J=6.56 Hz, 3H). LCMS: (Method A) 149.0 (M−16), Rt.1.65 min, 99.56% (Max). HPLC: (Method A) Rt. 1.60 min, 99.61% (Max).Chiral HPLC: (Method B) Rt 11.11 min, 100%.

Step 4: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-tosylpiperazine

To a stirred solution of (S)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine(41 g, 248 mmol) in DIPEA (86.6 mL, 496 mmol),N,N-bis(2-chloroethyl)-p-toluene sulfonamide (80.74 g, 273 mmol) wasadded at rt and the resulting mixture was heated at 105° C. overnight.The completion of the reaction was confirmed by TLC and the reactionmixture was diluted with water (1000 mL) and extracted with EtOAc (2×500mL). The combined organic layer was washed with water (200 mL), brinesolution (200 mL) and dried over Na₂SO₄. After evaporation of thesolvent, the resulting crude solid was suspended in pet ether (350 mL)and stirred for 10 min at rt. The suspension was filtered and was washedwith Et₂O (2×200 mL) and dried under vacuum to give the title compound.Yield: 63.2% (61 g, Off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.59(d, J=8.2 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 6.81-6.77 (m, 1H), 6.69 (d,J=7.4 Hz, 1H), 5.96 (s, 2H), 3.32 (q, J=7.76 Hz, 1H), 2.81-2.80 (m, 4H),2.42 (s, 3H), 2.36-2.32 (m, 4H), 1.18 (d, J=6.4 Hz, 3H). LCMS: (MethodA) 389.2 (M+H), Rt. 3.40 min, 98.09% (Max). HPLC: (Method A) Rt. 3.30min, 98.69% (Max). Chiral HPLC: (Method D) Rt. 15.79 min, 100.00%

Step 5: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazinehydrochloride

To a mixture of(S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-tosylpiperazine (61 g, 157mmol) and 4-hydroxy benzoic acid (65.01 g, 471 mmol), HBr in acetic acid(244 mL) was added at 0° C. and the reaction mixture was stirred at rtovernight. The completion of the reaction was confirmed by TLC. Thereaction mixture was diluted with water (400 mL). The precipitate wasfiltered through celite bed and washed with water (200 mL). The aqueousfilterate was washed with EtOAc (4×300 mL) and basified up to pH 11 withNaOH pellet (30 g) at 0° C. (during basification the colour of aqueouswas converted to light back). The product was extracted with EtOAc(4×300 mL). The combined organic layer was dried over Na₂SO₄ andevaporated under vacuum. The resulting light black oil was diluted in1,4 Dioxane (50 mL) and cooled to 0° C. and 4.5 N HCl solution indioxane (100 mL) was added and stirred for 15 min at rt. The solvent wasevaporated at 45° C. under reduced pressure to get the title compound(pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1H), 7.32 (s,1H), 7.06-6.99 (m, 2H), 6.07 (s, 2H), 4.55-4.52 (m, 1H), 3.80-3.61 (m,2H), 3.05-2.95 (m, 2H), 2.51-2.50 (m 4H), 1.68 (s, 3H). LCMS: (Method A)235.3 (M+H), Rt. 1.53 min, 95.85% (Max). HPLC: (Method A) Rt. 1.52 min,95.06% (Max). Chiral HPLC: (Method A) Rt. 8.11 min, 100%.

Intermediate 17 5-(1-chloroethyl)benzo[d]thiazole

Step 1: 1-(benzo[d]thiazol-5-yl)ethan-1-one

The title compound was prepared according to the procedure described forIntermediate 6, Step 1, using 5-bromobenzo[d]thiazole (3 g, 14 mmol) asstarting material. The crude product was purified by flashchromatography to give the title compound. Yield: 64.5% (1.6 g, paleyellow solid). LCMS: (Method A) 178.0 (M+H), Rt. 2.61 min, 81.8% (Max).

Step 2: 1-(benzo[d]thiazol-5-yl)ethan-1-ol

To a stirred solution of 1-(benzo[d]thiazol-5-yl)ethan-1-one (1.6 g, 9.0mmol) in methanol (20 mL), sodium borohydride (683 mg, 18 mmol) wasadded slowly at 0° C. and stirred 1.5 h. The completion of the reactionwas monitored by TLC and the solvents were evaporated at 45° C. undervacuum. The residue was diluted with EtOAc (50 mL) and washed with water(50 mL), brine solution (50 mL) and dried over Na₂SO₄. The organic layerwas evaporated at 40° C. to give the title compound. Yield: 91.9% (1.49g, pale brown solid). LCMS: (Method A) 180.0 (M+H), Rt. 2.35 min, 92.8%(Max).

Step 3: 5-(1-chloroethyl)benzo[d]thiazole

The title was synthesized from 1-(benzo[d]thiazol-5-yl)ethan-1-ol (1.49g, 8.3 mmol), according the general procedure B. The crude product wasused in the next step without further purification. Yield: quantitative(1.64 g, pale yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.43 (s, 1H),8.19-8.17 (m, 2H), 7.63-7.61 (m, 1H), 5.57-5.52 (m, 1H), 1.87 (d, J=6.7Hz, 3H). LCMS: (Method A) 198.0 (M+H), Rt. 3.98 min, 62.0% (Max).

Intermediate 18 5-(1-chloroethyl)-2,2-difluorobenzo[d][1,3]dioxole

Step 1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-one

The title compound was prepared according to the procedure described forIntermediate 6, Step 1, using 5-bromo-2,2-difluorobenzo[d][1,3]dioxole(3 g, 12.6 mmol) as starting material. The crude product was purified byflash chromatography to give the title compound. Yield: 94.86% (2.4 g,pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.94-7.91 (m, 1H),7.90-7.88 (m, 1H), 7.55 (d, J=8.4 Hz), 2.57 (s, 3H).

Step 2: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-ol

The title compound was prepared according to the procedure described forIntermediate 17, Step 2, using1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-one (2.5 g, 12.4 mmol)as starting material. After evaporation of the solvent, the titleproduct was isolated and used in the next without further purification.Yield: 91.08% (2.3 g, Black liquid). ¹H NMR (400 MHz, DMSO-d₆): δ7.34-7.30 (m, 2H), 7.17-7.14 (m, 1H), 4.75-4.69 (m, 1H), 1.29 (d, J=6.4Hz, 3H).

Step 3: 5-(1-chloroethyl)-2,2-difluorobenzo[d][1,3]dioxole

The title compound was synthesized from1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-ol (1 g, 4.9 mmol),according the general procedure B. Yield: 92.5% (1 g, black gel). ¹H NMR(400 MHz, DMSO-d₆): δ 7.59 (d, J=2 Hz, 1H), 7.41-7.38 (m, 1H), 7.34-7.31(m, 1H), 5.38 (q, J=6.8 Hz, 1H), 1.78 (d, J=8 Hz, 3H).

Intermediate 19 5-(1-chloroethyl)benzo[c][1,2,5]thiadiazole

Step 1: 1-(benzo[c][1,2,5]thiadiazol-5-yl)ethan-1-one

The title compound was prepared according to the procedure described forIntermediate 6, Step 1, using 5-bromobenzo[c][1,2,5]thiadiazole (3 g,13.9 mmol) as starting material. The crude product was purified by flashchromatography to give the title compound. Yield: 76.61% (1.9 g, palebrown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.84 (s, 1H), 8.20-8.13 (m,2H), 2.76 (s, 3H). LCMS: (Method A) 178.9 (M+H), Rt. 4.81 min, 43.23%(Max).

Step 2: 1-(benzo[c][1,2,5]thiadiazol-5-yl)ethan-1-ol

The title compound was prepared according to the procedure described forIntermediate 17, Step 2, using1-(benzo[c][1,2,5]thiadiazol-5-yl)ethan-1-one (1.9 g, 10.6 mmol) asstarting material. After evaporation of the solvent, the title compoundwas isolated and used without further purification. Yield: 88.5% (1.7 g,dark brown liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.02 (d, J=9.08 Hz,1H), 7.95 (s, 1H), 7.74-7.71 (m, 1H), 5.50 (d, J=4.36 Hz, 1H), 4.93-4.88(m, 1H), 1.40 (d, J=6.48 Hz, 3). LCMS: (Method A) 181.0 (M+H), Rt. 2.05min, 95.01% (Max).

Step 3: 5-(1-chloroethyl)benzo[c][1,2,5]thiadiazole

The title compound was synthesized from1-(benzo[c][1,2,5]thiadiazol-5-yl)ethan-1-ol (1.7 g, 9.4 mmol),according the general procedure B. The crude product was used in thenext step without further purification. Yield: quantitative (1.9 g,brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.17-8.12 (m, 2H), 7.88-7.85(m, 1H), 5.62-5.57 (m, 1H), 1.89 (d, J=6.76 Hz, 3H).

Intermediate 20 3-chloro-7-(1-chloroethyl)quinoline

Step 1: 1-(3-chloroquinolin-7-yl) ethan-1-one

The title compound was prepared according to the procedure described forIntermediate 6, Step 1, using 7-bromo-3-chloroquinoline (1 g, 4.12 mmol)as starting material. The crude product was purified by flashchromatography to give the title compound. Yield: 71.5% (0.6 g, paleyellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.02 (s, 1H), 8.69-8.66 (m,2H), 8.14-8.07 (m, 2H), 2.75 (s, 3H).

Step 2: 1-(3-chloroquinolin-7-yl) ethan-1-ol

The title compound was prepared according to the procedure described forIntermediate 17, Step 2, using 1-(3-chloroquinolin-7-yl)ethan-1-one (0.6g, 2.9 mmol) as starting material. After evaporation of the solvent, thetitle compound was isolated and used without further purification.Yield: 99.2% (0.6 g, pale yellow oil). ¹H NMR (400 MHz, DMSO-d₆): δ8.87-8.86 (d, J=2.48 Hz, 1H), 8.54 (s, 1H), 7.98-7.93 (m, 2H), 7.69-7.67(m, 1H), 5.45 (d, J=4.4 Hz, 1H), 4.95-4.93 (m, 1H), 1.41 (d, J=6.48 Hz,3H). LCMS: (Method A) 208.0 (M+H), Rt. 2.59 min, 96.46% (Max).

Step 3: 3-chloro-7-(1-chloroethyl)quinoline

The title was synthesized from 1-(3-chloroquinolin-7-yl)ethan-1-ol(0.600 g, 2.89 mmol), according to the general procedure B. The crudeproduct was used in the next step without further purification. Yield:quantitative (0.655 g, pale yellow oil). LCMS: (Method A) 227.9 (M+H),Rt. 4.55 min, 90.09% (Max).

Intermediate 21 6-(1-chloroethyl)-2,3-dihydrobenzofuran

Step 1: 1-(2,3-dihydrobenzofuran-6-yl)ethan-1-one

The title compound was prepared according to the procedure described forIntermediate 6, Step 1, using 6-bromo-2,3-dihydro-1-benzofuran (1 g,5.03 mmol) as starting material. The crude product was purified by flashchromatography to give the title compound. Yield: 73.7% (0.6 g, paleyellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.48 (d, J=7.64 Hz, 1H),7.37-7.35 (d, J=7.68 Hz, 1H), 7.26 (s, 1H), 4.58 (t, J=8.76 Hz, 2H),3.24 (t, J=8.76 Hz, 2H), 2.53 (s, 3H). LCMS: (Method A) 163.2 (M+H), Rt.3.01 min, 97.60% (Max).

Step 2: 1-(2,3-dihydrobenzofuran-6-yl)ethan-1-ol

The title compound was prepared according to the procedure described forIntermediate 17, Step 2, using 1-(2,3-dihydrobenzofuran-6-yl)ethan-1-one(0.6 g, 3.7 mmol) as starting material. After evaporation of thesolvent, the title compound was isolated and used without furtherpurification. Yield: 88.30% (0.53 g, colourless liquid). ¹H NMR (400MHz, DMSO-d₆): δ 7.11 (d, J=7.6 Hz, 1H), 6.77-6.75 (m, 1H), 6.71 (s,1H), 5.04 (d, J=4.4 Hz, 1H), 4.63-4.61 (m, 1H), 4.48 (t, J=8.8 Hz, 2H),3.11 (t, J=8.8 Hz, 2H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method A) 147.0(M−17H), Rt. 2.64 min, 89.95% (Max).

Step 3: 6-(1-chloroethyl)-2,3-dihydrobenzofuran

The title compound was synthesized from1-(2,3-dihydrobenzofuran-6-yl)ethan-1-ol (0.53 g, 3.23 mmol), accordingto the general procedure B. The crude product was used in the next stepwithout further purification. Yield: quantitative (0.58 g, brown oil).¹H NMR (400 MHz, DMSO-d₆): δ 7.20 (d, J=7.56 Hz, 1H), 6.93-6.91 (m, 1H),6.87 (s, 1H), 5.29-5.24 (m, 1H), 4.53 (t, J=8.72 Hz, 2H), 3.15 (t,J=8.76 Hz, 2H), 1.75 (d, J=6.76 Hz, 3H). LCMS: (Method A) 147.0 (M−35H),Rt. 3.76 min, 83.62% (Max).

Intermediate 22 1,2-Dichloro-4-(1-chloroethyl)benzene

Step 1: 1-(3,4-Dichlorophenyl)ethan-1-ol

To a stirred solution of 3,4-dichloroacetophenone (4 g, 21.15 mmol,Aldrich) in dry MeOH (80 mL), sodium borohydride (0.96 g, 25.39 mmol,spectrochem) was added portionwise at 0° C. The reaction mixture wasstirred at rt overnight. It was cooled to 0° C. and quenched using icewater (10 mL). Solvents were removed under reduced pressure andresulting residue was dissolved in DCM (50 mL). The organic layer waswashed with water (25 mL), brine (20 mL), dried over Na₂SO₄ andconcentrated. The crude product was used for next step without furtherpurification. Yield: 95% (3.8 g, colorless liquid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.57-7.55 (m, 2H), 7.33 (d, J=1.9 Hz, 1H), 5.38 (d, J=4.4Hz, 1H), 4.76-4.70 (m, 1H), 1.30 (d, J=6.4 Hz, 3H).

Step 2: 1,2-Dichloro-4-(1-chloroethyl)benzene

The title compound was synthesized by following general procedure B,using 1-(3,4-dichlorophenyl)ethan-1-ol (1.5 g, 7.85 mmol) and thionylchloride (1.14 mL, 15.7 mmol) as starting materials. It was used in thenext step without further purification. Yield: 97% (1.6 g, colorlessliquid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.75 (s, 1H), 7.65-7.43 (m, 2H),5.74-5.32 (m, 1H), 1.35 (d, J=8.5 Hz, 3H).

Intermediate 23 3-(1-chloroethyl)quinoline

Step 1: 1-(quinolin-3-yl)ethan-1-ol

To a stirred solution of 1-(quinolin-3-yl)ethan-1-one (1 g, 5.85 mmol)in methanol (10 mL), sodium borohydride (442 mg, 11.7 mmol) was addedslowly at 0° C. The reaction was stirred for 2 h at rt. The completionof reaction was monitored by TLC. The reaction mixture was evaporated at45° C. under vacuum. The resulting mixture was diluted with EtOAc (100mL), washed with water (50 mL), brine (50 mL) and dried over anhydrousNa₂SO₄. After evaporation of the solvents, the title compound wasisolated and used for the next step without any further purification.Yield: 89.1% (900 mg, pale brown solid). LCMS: (Method A) 174.0 (M+H),Rt. 1.37 min, 99.3% (Max).

Step 2: 3-(1-chloroethyl)quinoline

The compound 3-(1-chloroethyl)quinoline was synthesized from1-(quinolin-3-yl)ethan-1-ol (900 mg, 5.2 mmol), according to the generalprocedure B. Yield: quantitative (993 mg, off white solid). ¹H NMR (400MHz, DMSO-d₆): δ 8.64 (s, 1H), 6.90-6.85 (m, 2H), 6.77-6.73 (m, 1H),5.78-5.75 (m, 2H), 4.13-4.09 (m, 1H), 3.19-3.15 (m, 4H), 2.53-2.49 (m,4H), 1.27 (d, J=6.6 Hz, 3H). LCMS: (Method A) 192.0 (M+H), Rt. 2.28 min,99.4% (Max).

Intermediate 24 (R)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine

Step 1:(R)-N-(1-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide

To a mixture of 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-one (260 g, 1584mmol), (R)-(+)-2-Methyl-2-propanesulfinamide (210.3 g, 1742 mmol) in THF(2.3 L) titanium(IV)ethoxide (722 g, 3168 mmol) was added at rt over 30min and refluxed for 30 h. Reaction was monitored by HPLC. The reactionmass was cooled to rt and slowly quenched with water (1000 mL). Theprecipitate observed was filtered through celite bed (350 g) and thefiltration cake was washed with ethylacetate (2×1.5 L). The combinedorganic layer was washed with water (1.5 L), brine solution (1.5 L) anddried over sodium sulfate (250 g) and evaporated under vacuum at 50° C.The resulted crude was co-distilled with toluene (2×1000 mL) and used assuch for next step. Yield: quantitative (580 g, brown liquid). HPLC:(Method A) Rt. 3.83 min, 53.3% (Max).

Step 2:(R)-N-((R)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpropane-2-sulfinamide

To a stirred solution of(R)-N-(1-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide(6 g, 22.0 mmol) in THF (100 mL), sodium borohydride (2.5 g, 67.4 mmol)was added slowly at 0° C. and then stirred at rt for 1 h. Completion ofthe reaction was confirmed by TLC. The precipitate observed was filteredthrough celite bed (30 g) and was washed with EtOAc (2×50 mL). Theorganic layer was washed with water (50 mL), brine (50 mL) and driedover Na₂SO₄ (20 g) and evaporated under vacuum at 50° C. The resultingcrude product was purified by flash chromatography (25% EtOAc in petether) to give the title compound. Yield: 66.2% (4 g, off white solid).¹H NMR (400 MHz, DMSO-d₆): δ 6.97 (s, 1H), 6.83-6.77 (m, 2H), 5.97-5.96(m, 2H), 5.25 (d, J=7.1 Hz, 1H), 4.30-4.23 (m, 1H), 1.33 (d, J=6.8 Hz,3H), 1.08 (s, 9H). LCMS: (Method A) 270.0 (M+H), Rt. 3.79 min, 96.41%(Max). HPLC: (Method A) Rt. 3.76 min, 96.84% (Max). Chiral HPLC: (MethodC) Rt. 7.71 min, 97.5%.

Step 3: (R)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine

To a stirred solution of(R)-N-((R)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpropane-2-sulfinamide(4 g, 14.86 mmol) in MeOH (20 mL), methanolic hydrochloride (18.5 mL,74.3 mmol, 4M) was added at 0° C. over 15 min and stirred at rt for 1 h.Completion of the reaction was confirmed by TLC. Then the reactionmixture was concentrated under vacuum at 50° C. To the resulting crude,EtOAc (50 mL) was added and filtered and filtration cake was washed withEtOAc (50 mL). The solid hydrochloride salt was basified by aq. ammonia(30% w/v, 25 mL) and extracted with EtOAC (2×50 mL). The combinedorganic layer was washed with brine solution (1×50 mL) and dried overNa₂SO₄. The solvent was evaporated at under vacuum to give the titlecompound. Yield: 85% (2.1 g, brown liquid). ¹H NMR (400 MHz, DMSO-d₆): δ6.95 (s, 1H), 6.81-6.77 (m, 2H), 5.95-5.93 (m, 2H), 3.90 (q, J=6.5 Hz,1H), 1.86-1.85 (brs, 2H), 1.17 (d, J=6.5 Hz, 3H). LCMS: (Method A) 149.0(M −16), Rt. 1.66 min, 96.9% (Max). HPLC: (Method A) Rt. 1.59 min,96.86% (Max). Chiral HPLC: (Method B) Rt. 7.12 min, 97.76%.

Step 3: (R)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-tosylpiperazine

To a stirred solution of (R)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine(2 g, 12.1 mmol) in DIPEA (4.22 mL, 24.2 mmol),N,N-bis(2-chloroethyl)-p-toluene sulfonamide (3.9 g, 13.3 mmol) wasadded at rt and the resulting mixture was heated to 105° C. for 18 h.Completion of the reaction was confirmed by TLC. Reaction mixture wasdiluted with water (30 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layer was dried over Na₂SO₄ and evaporated undervacuum. To the resulting crude solid hexane (50 mL) was added, and theresulting mixture was stirred for 10 min at rt. It was filtered and thesolid was washed with Et₂O (2×50 mL) and dried under vacuum to give thetitle compound. Yield: 63.8% (3 g, off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.59 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.81-6.77(m, 2H), 6.69-6.6 (m, 1H), 5.97-5.95 (m, 2H), 3.35-3.31 (m, 1H),2.81-2.80 (m, 4H), 2.42 (s, 3H), 2.36-2.32 (m, 4H), 1.18 (d, J=6.8 Hz,3H). LCMS: (Method A) 389.0 (M+H), Rt. 3.39 min, 98.9% (Max). HPLC:(Method A) Rt. 3.30 min, 99.53% (Max), Chiral HPLC: (Method A) Rt. 15.54min, 97.58%.

Step 5: (R)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine

To the reaction mixture of(R)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-tosylpiperazine (2.7 g, 6.9mmol) and 4-hydroxy benzoic acid (2.8 g, 20.8 mmol), HBr in acetic acid(30% w/v, 14 mL) was added at 0° C. and stirred overnight at rt.Completion of the reaction was confirmed by TLC. Reaction mixture wasdiluted with water (60 mL) and the resulting precipitate was filteredthrough a celite bed. The celite bed was washed with water (50 mL). Theaqueous layer was washed with EtOAc (4×50 mL) and basified up to pH 11with NaOH pellet (10 g) at 0° C. The product was extracted with EtOAc(3×30 mL). The combined organic layer was dried over Na₂SO₄ andevaporated under vacuum to give the title compound. Yield: 92% (1.5 g,Dark brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.84-6.81 (m, 2H),6.72-6.71 (m, 1H), 5.97-5.95 (m, 2H), 3.29-3.23 (m, 2H), 2.64-2.62 (m,4H), 2.26-2.19 (m, 4H), 1.22 (d, J=6.8 Hz, 3H). LCMS: (Method A) 235.3(M+H), Rt. 1.56 min, 96.9% (Max). HPLC: (Method A) Rt. 1.50 min, 96.9%(Max). Chiral HPLC: (Method A) Rt. 10.13 min, 98.04%.

Intermediate 252-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-onedihydrochloride

Step 1: tert-butyl 3-bromo-2,4-dioxopiperidine-1-carboxylate

To a stirred solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (1g, 4.69 mmol) in dry CCl₄ (10 mL), N-bromosuccinimide (0.83 g, 4.69mmol) was added at 10° C. The reaction mixture was stirred at 10-15° C.for 2 h. It was then evaporated under reduced pressure. Water (10 mL)was added and the desired product was extracted with EtOAc (2×30 mL).The combined organic layer was dried over Na₂SO₄ and concentrated. Theresulting crude product was purified by flash column chromatography,affording the title product. Yield: 99% (1.4 g, off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 5.50 (s, 1H), 3.74-3.71 (m, 2H), 2.69-2.66 (m,2H), 1.46 (s, 9H). LCMS: (Method A) 193.8 (M-Boc+H), Rt. 2.93 min,81.51% (Max).

Step 2:tert-butyl-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-oxo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 1.31 g, 5.36 mmol) in isopropanol (15 mL), tert-butyl3-bromo-2,4-dioxopiperidine-1-carboxylate obtained in the first step(1.3 g, 4.46 mmol) was added at rt. The reaction mixture was stirredovernight at 90° C. It was cooled down to rt and evaporated underreduced pressure. Water (10 mL) was added and the desired product wasextracted with diethyl ether (2×30 mL), dried over Na₂SO₄ andconcentrated, affording the title product. Yield: 74% (1.42 g, yellowsolid). LCMS: (Method A) 239.0 (M-Boc+H), Rt. 0.70 min, 48.39% (Max).

Step 3: 2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-onedihydrochloride

To a stirred solution oftert-butyl-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-oxo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylateobtained in previous step (1.3 g, 2.96 mmol) in 1,4-dioxane (10 mL), HClin dioxane (4 M solution, 13 mL, 10 V) was added at 0° C. The reactionmixture was stirred for 2 h at rt. It was evaporated and DCM (15 mL) wasadded and evaporated. This procedure was repeated twice, affording thetitle product which was used without any further purification. Yield:99% (0.82 g, off white solid).

Intermediate 26 5-(1-chloroethyl)-2-methylbenzo[d]thiazole

Step 1: 2-methylbenzo[d]thiazole-5-carboxylic acid

4-Chloro-3-nitrobenzoic acid (10 g, 50.25 mmol) and sodium sulfide (33.3g, 427 mmol) were heated up to melting and stirred for 20 min. Thenreaction mixture was cooled to rt and acetic anhydride (11.7 mL, 115mmol) and acetic acid (4.3 mL, 75.3 mmol) were added. The resultingreaction mixture was refluxed for 20 min and cooled to rt. Water (50 mL)and EtOAc (100 mL) were added and the mixture was stirred for 20 min.The resulting mass was filtered through celite, washed with EtOAc (50mL). The combined filtrate was washed with brine (30 mL), dried overNa₂SO₄ and concentrated. The celite plug was further washed with EtOH(3×100 mL) and the filtrate was filtered through silica gel andconcentrated under reduced pressure. Both fractions were mixed and takenfor next step without further purification (brown solid). ¹H NMR (400MHz, DMSO-d₆): δ 9.88 (s, 1H), 8.33 (s, 1H), 7.92-7.88 (m, 2H), 2.79 (s,3H). LCMS: (Method A) 194.0 (M+H), Rt. 2.73 min, 59.03% (Max).

Step 2: (2-methylbenzo[d]thiazol-5-yl)methanol

To a stirred solution of 2-methylbenzo[d]thiazole-5-carboxylic acidobtained in the previous step (3.7 g, 19.7 mmol) in dry THF (35 mL),lithium aluminium hydride (2 M in THF, 19.2 mL, 38.34 mmol) was added at0° C. and the resulting mixture was stirred at rt for 1 h. It was cooledto 0° C., quenched with saturated Na₂SO₄ solution and filtered throughcelite. The filtrate was diluted with EtOAc (50 mL), washed with brine(10 mL), water (10 mL) and dried over Na₂SO₄. After evaporation of thesolvent, the resulting crude product was taken for next step withoutfurther purification (yellow oil). LCMS: (Method A) 180.0 (M+H), Rt.1.95 min, 40.76% (Max).

Step 3: 2-methylbenzo[d]thiazole-5-carbaldehyde

To a stirred solution of (2-methylbenzo[d]thiazol-5-yl)methanol (0.6 g,3.35 mmol) in dry DCM (6 mL), NaHCO₃ (1.12 g, 13.4 mmol) followed byDess-Martin periodinane (2.84 g, 6.70 mmol) were added and the reactionmixture was stirred at rt for 2 h. It was diluted with DCM (50 mL) andwashed with water (15 mL), 10% NaHCO₃ solution (15 mL), brine (15 mL)and dried over Na₂SO₄. The title product was obtained after evaporationof the solvents. Yield: 99% (0.65 g, brown liquid). ¹H NMR (400 MHz,DMSO-d₆): δ 10.12 (s, 1H), 8.25 (s, 1H), 7.80-7.79 (m, 2H), 2.86 (s,3H). LCMS: (Method A) 178.0 (M+H), Rt. 2.84 min, 81.57% (Max).

Step 4: 1-(2-methylbenzo[d]thiazol-5-yl)ethan-1-ol

To a stirred solution of 2-methylbenzo[d]thiazole-5-carbaldehyde (0.65g, 3.67 mmol) in THF (6 mL), methyl magnesium bromide (1.4M inTHF:Toluene 1:3 mixture, 3.9 mL, 5.50 mmol) was added at 0° C. Thereaction mixture was stirred for 1 h at rt and was then quenched withsaturated NH₄Cl (5 mL) at 0° C. It was diluted with EtOAc (30 mL),washed with water (10 mL), brine (10 mL) and dried over Na₂SO₄. Thetitle product was obtained after evaporation of the solvents (brownliquid). ¹H NMR (400 MHz, DMSO-d₆): δ7.97-7.95 (m, 1H), 7.51-7.50 (m,2H), 5.29 (d, J=4.4 Hz, 1H), 4.87-4.86 (m, 1H), 2.78 (s, 3H), 1.37 (d,J=6.4 Hz, 3H). LCMS: (Method A) 194.0 (M+H), Rt. 2.53 min, 73.53% (Max).

Step 5: 5-(1-chloroethyl)-2-methylbenzo[d]thiazole

To a stirred solution of 1-(2-methylbenzo[d]thiazol-5-yl)ethan-1-ol(0.35 g, 3.67 mmol) in DCM (5 mL), thionyl chloride (0.27 mL, 3.62 mmol)was added at 0° C. The reaction mixture was stirred for 1 h at rt andconcentrated. DCM (15 mL) was added and was evaporated. This procedurewas repeated a second time, affording the title product. It was used inthe next step without any further purification. Yield: 90% (0.38 g,brown liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.01-8.00 (m, 2H), 7.54-7.52(m, 1H), 5.53-5.51 (m, 1H), 2.80 (s, 3H), 1.86 (d, J=6.8 Hz, 3H). LCMS:(Method A) 212.0 (M+H), Rt. 2.61 min, 58.89% (Max).

Intermediate 27 6-(1-chloroethyl)benzo[d]thiazole

Step 1: 1-(benzo[d]thiazol-6-yl)ethan-1-one

A solution of 6-bromobenzo[d]thiazole (1.2 g, 5.61 mmol) in dry toluenewas put under inter atmosphere. 1-Ethoxy vinyl tributyltin (3.0 g, 8.41mmol) and bis(triphenylphosphine)palladium dichloride (0.39 g, 0.56mmol) were added at rt and the resulting mixture was stirred overnightat 90° C. It was cooled to rt and filtered through celite. The filtratewas concentrated under vacuum and the resulting crude product wasstirred in HCl aqueous solution (6 N, 20 mL) for 1 h at rt. The solutionwas concentrated and neutralized with saturated NaHCO₃ solution. Thedesired product was extracted with DCM (60 mL), dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. It was purified by flashcolumn chromatography to afford the title compound. Yield: 60% (0.6 g,yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.59 (s, 1H), 8.88 (s, 1H),8.17 (d, J=8.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 2.75 (s, 3H). LCMS:(Method A) 178.0 (M+H), Rt. 1.97 min, 94.50% (Max).

Step 2: 1-(benzo[d]thiazol-6-yl)ethan-1-ol

To a stirred solution of 1-(benzo[d]thiazol-6-yl)ethan-1-one, obtainedin the previous step (0.6 g, 3.39 mmol) in dry MeOH (20 mL), sodiumborohydride (0.38 g, 10.2 mmol) was added portion wise at 0° C. and themixture was stirred at rt for 1 h. It was concentrated, diluted with DCM(50 mL), washed with water (15 mL), brine (10 mL) and dried over Na₂SO₄.After evaporation of the solvent, the title product was obtained and wasused in the next step without any further purification. Yield: 66% (0.4g, brown liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.40 (s,1H), 7.80 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 4.88 (d, J=2.8 Hz,1H), 4.37 (d, J=2.8 Hz, 1H), 1.92 (s, 3H).

Step 3: 6-(1-chloroethyl)benzo[d]thiazole

To a stirred solution of 1-(benzo[d]thiazol-6-yl)ethan-1-ol (0.4 g, 2.25mmol) in dry DCM (20 mL), thionyl chloride (0.3 mL, 4.5 mmol) was addeddropwise at 0° C. and the resulting reaction mixture was stirred at rtfor 1 h. It was concentrated. DCM (5 mL) was added and was evaporatedagain. This procedure was repeated twice, affording the title productthat was used without any further purification. Yield: 98% (430 mg,brown liquid).

Intermediate 28 7-(1-Chloroethyl)-3-methylquinoline

Step 1: 7-Bromo-3-methylquinoline

To a solution of 4-bromo-2-nitrobenzaldehyde (5 g, 21.7 mmol) in ethanol(50 mL), iron powder (4.85 g, 86.9 mmol) was added followed by HClaqueous solution (0.1 N, 15 mL). The resulting reaction mixture wasvigorously stirred at 95° C. for 2 h. The reaction progression wasfollowed by TLC. When the reduction was completed, propionaldehyde (1.5mL, 21.7 mmol) and KOH (1.46 g, 26.0 mmol, in two portions) were addedat rt. The reaction mixture was stirred at 95° C. overnight. It wascooled to rt, diluted with DCM (30 mL) and filtered through celite. Thefiltrate was washed with water (50 mL) and the aqueous layer wasextracted with DCM (2×100 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude product was purified by flash chromatography, affording the titlecompound. Yield: 52% (2.5 g, Pale yellow solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.81 (s, 1H), 8.18-8.17 (m, 2H), 7.89 (d, J=8.7 Hz, 1H),7.72 (dd, J=1.9, 8.7 Hz, 1H), 2.50 (s, 3H). LCMS: (Method D) 223.9(M+H), Rt. 2.48 min, 99.58% (Max).

Step 2: 1-(3-Methylquinolin-7-yl)ethan-1-one

A stirred solution of 7-bromo-3-methylquinoline obtained in previousstep (2 g, 9.0 mmol) in toluene (20 mL) was flushed with nitrogen for15-20 min. 1-Ethoxy-1-(tributylstannyl)ethylene (3.9 mL, 11.7 mmol) andbis(triphenylphosphine)palladium dichloride (0.31 g, 0.45 mmol) wereadded and the resulting reaction mixture was stirred at 90° C. for 12 h.It was cooled to rt, filtered through celite and concentrated underreduced pressure. HCl aqueous solution (6 N, 30 mL) was added and themixture was stirred at room temperature for 1 h. The solution wasneutralized with the addition of solid sodium bicarbonate and wasextracted with EtOAc (2×50 mL). The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated. The crude product was purifiedby flash chromatography, affording the title compound. Yield: 60% (1.1g, pale yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.90 (s, 1H), 8.61(s, 1H), 8.21 (s, 1H), 8.04-7.98 (m, 2H), 2.76 (s, 3H), 2.52 (s, 3H).LCMS: (Method D) 186.0 (M+H), Rt. 1.88 min, 99.85% (Max).

Step 3: 1-(3-Methylquinolin-7-yl)ethan-1-ol

To a stirred solution of 1-(3-methylquinolin-7-yl)ethan-1-one obtainedin previous step (1.1 g, 5.9 mmol) in MeOH (12 mL), sodium borohydride(0.26 g, 7.1 mmol) was added portion wise at 0° C. and the reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas concentrated under reduced pressure and the resulting crude waterwas added and extracted with DCM (2×50 mL). The combined organic layerwas dried over anhydrous sodium sulphate, concentrated under reducedpressure and the crude mass was purified by column chromatography toafford the title compound. Yield: 55% (0.8 g, yellow solid). ¹H NMR (400MHz, DMSO-d₆): δ 8.73 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.82 (d,J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 5.33 (d, J=4.4 Hz, 1H), 4.94-4.89(m, 1H), 2.47 (s, 3H), 1.41 (d, J=6.4 Hz, 3H). LCMS: (Method D) 188.1(M+H), Rt. 0.83 min, 94.19% (Max).

Step 4: 7-(1-Chloroethyl)-3-methylquinoline

To a stirred solution of 1-(3-methylquinolin-7-yl)ethan-1-ol obtained inprevious step (0.8 g, 4.2 mmol) in DCM (8 mL), thionyl chloride (0.61mL, 8.5 mmol) was added drop wise at 0° C. and the resulting mixturestirred at room temperature for 1 h. The reaction completion wasconfirmed by TLC. The reaction mixture was concentrated under reducedpressure and the resulting crude product was used in the next stepwithout any further purification. Yield: 85% (0.75 g, brown solid). ¹HNMR (400 MHz, DMSO-d₆): δ 9.06 (s, 1H), 8.60 (s, 1H), 8.18 (s, 1H), 8.13(d, J=8.8 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 5.68-5.63 (m, 1H), 2.57 (s,3H), 1.90 (d, J=6.8 Hz, 3H). LCMS: (Method D) 206.0 (M+H), Rt. 2.12 min,91.94% (Max).

Intermediate 29 1-(3-(Trifluoromethyl)pyridin-2-yl)piperazine

To a stirred solution of 2-chloro-3-(trifluoromethyl)pyridine (1 g, 5.50mmol) in n-Butanol (10 mL), 1-piperazine (6.63 g, 77.12 mmol) was addedand the reaction mixture was stirred at 100° C. for 24 h. The reactioncompletion was confirmed by TLC. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. The resultingmixture was diluted with ethyl acetate (30 mL) and neutralized withsaturated sodium bicarbonate solution (4 mL), and extracted with EtOAc(2×50 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude was purified bycolumn chromatography to afford the title compound. Yield: 63% (0.8 g,colorless gum). ¹HNMR (400 MHz, DMSO-d₆): δ 8.50 (d, J=3.6 Hz, 1H), 8.03(dd, J=7.8, 2.0 Hz, 1H), 7.16-7.13 (m, 1H), 3.11-3.08 (m, 4H), 2.81-2.79(m, 4H). LCMS: (Method F) 232.0 (M+H), Rt. 2.10 min, 96.01% (Max).

EXAMPLES Example 12-(1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperidin-4-yl)-4-methylthiazole

Step 1: 1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid

To a stirred solution of isonipecotic acid (6.0 g, 46.6 mmol) intert-BuOH (18 mL), NaOH solution (12 mL, 3.71 g, 92.8 mmol in 12 mLwater) was added at 10-15° C., followed by di-tert-butyl dicarbonate(10.1 g, 46.6 mmol) and the mixture was stirred at rt for 3 h. Thecompletion of the reaction was monitored by TLC. The reaction mixturewas diluted with water and washed with petroleum ether (3×25 mL). The pHof the aqueous layer was adjusted to 6-6.5 using citric acid and wasextracted with DCM. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the title compound.Yield: 73% (10.0 g, white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.25 (s,1H), 3.83-3.80 (m, 2H), 2.80-2.49 (m, 2H), 2.39-2.36 (m, 1H), 1.79-1.75(m, 2H), 1.41-1.34 (m, 11H).

Step 2: tert-Butyl 4-carbamoylpiperidine-1-carboxylate

To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylicacid (10.0 g, 43.6 mmol) in dry THF (150 mL), CDI (9.95 g, 65.6 mmol)was added at 0-5° C. and the reaction mixture was stirred at rt for 16h. Then the reaction mixture was cooled to 0-5° C. and a continuous flowof ammonia was applied to the solution for 2 h. MeOH (30 mL) was addedand the flow of ammonia was applied for 2 additional hours at the sametemperature. The reaction mixture was then stirred at rt for 16 h. Itwas concentrated under reduced pressure and the resulting crude mixturewas dissolved in EtOAc and washed with 10% citric acid, 10% sodiumbicarbonate, water, dried over anhydrous Na₂SO₄ and concentrated undervacuum to afford the title compound (white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 6.77 (s, 2H), 3.91-3.88 (m, 2H), 2.71-2.49 (m, 2H),2.25-2.17 (m, 1H), 1.66-1.62 (m, 2H), 1.39-1.35 (m, 13H). LCMS: (MethodA) 130.2 (M+H), Rt. 2.62 min, 99.0% (Max).

Step 3: tert-Butyl 4-carbamothioylpiperidine-1-carboxylate

To a stirred solution of tert-butyl 4-carbamoylpiperidine-1-carboxylate(1.3 g, 5.7 mmol) in THF (16 mL), Lawssen's reagent 2.53 g, 6.27 mmol)was added. The reaction mixture was refluxed for 6 h and then stirred atrt for 16 h. The completion of the reaction was monitored by TLC. Thereaction mixture was diluted with ethyl acetate and was washed with 10%citric acid, 10% sodium bicarbonate, water and brine, dried overanhydrous Na₂SO₄ and concentrated under vacuum to afford the titlecompound. Yield: 78% (1.09 g, colorless oil). ¹H NMR (400 MHz, DMSO-d₆):δ 9.41 (s, 1H), 9.11 (s, 1H), 4.03-3.97 (m, 1H), 2.66-2.61 (m, 2H),1.64-1.52 (m, 4H), 1.40 (s, 9H), 1.38-1.34 (m, 2H). LCMS: (Method A)245.2 (M+H), Rt. 3.38 min, 93.5% (Max).

Step 4: tert-Butyl 4-(4-methylthiazol-2-yl)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperidine-1-carboxylate (1.0 g, 4.1 mmol) in dioxane (10mL), triethyl amine (0.62 g, 6.5 mmol) and bromo acetone (0.84 g, 6.5mmol) were added and stirred at 90° C. for 16 h. The completion of thereaction was monitored by TLC. The reaction mixture was quenched withwater and extracted with DCM with 10% MeOH (5×25 mL). The organic layerwas separated, dried over anhydrous Na₂SO₄, concentrated under vacuumand was purified by flash chromatography (30% EtOAc in petroleum ether)to afford the title compound (colorless oil). LCMS: (Method A) 283.0(M+H), Rt. 3.35 min, 93.5% (Max).

Step 5: 4-Methyl-2-(piperidin-4-yl)thiazole hydrochloride

To a stirred solution of tert-butyl4-(4-methylthiazol-2-yl)piperidine-1-carboxylate (0.39 g, 1.38 mmol) indry dioxane (2 mL), HCl in dioxane (3 N, 10 mL) was added at rt and thereaction mixture was stirred for 2 h. It was then concentrated underreduced pressure and the crude product was triturated in diethyl ether,filtrated and dried under vacuum to afford the title compound. Yield:99% (0.3 g, white oil). LCMS: (Method B) 183.0 (M+H), Rt. 3.21 min,92.5% (Max).

Step 6:2-(1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperidin-4-yl)-4-methylthiazole

The title compound was synthesized by following general procedure E,using 4-methyl-2-(piperidin-4-yl)thiazole hydrochloride (0.3 g, 1.37mmol) and Intermediate 1 (0.379 g, 2.0 mmol). The reaction mixture wasstirred at 60° C. for 16 h. The crude product was purified by flashchromatography, affording the title compound (colorless oil). ¹H NMR(400 MHz, CDCl₃): δ 6.90 (s, 1H), 6.76-6.74 (m, 3H), 5.96 (s, 2H),3.41-3.39 (m, 1H), 3.17-3.14 (m, 1H), 2.94-2.92 (m, 2H), 2.42 (s, 3H),2.14-2.02 (m, 4H), 1.92-1.74 (m, 2H), 1.37 (d, J=6.8 Hz, 3H). LCMS:(Method A) 331.0 (M+H), Rt. 2.54 min, 95.5% (Max). HPLC: (Method A) Rt.2.54 min, 97.3% (Max).

Example 22-(1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidin-4-yl)-5-methyl-1,3,4-oxadiazole

Step 1: Ethyl1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxylate

The title compound was synthesized by following general procedure D,using 4-piperidine carboxylic acid ester (25 g, 159 mmol) andIntermediate 1 (49.87 g, 271 mmol). The crude product was purified byflash chromatography, affording the title compound (pale brown liquid).LCMS: (Method A) 306.0 (M+H), Rt. 2.71 min, 29.4% (Max).

Step 2: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carbohydrazide

To a stirred solution of ethyl1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxylate (4.3 g,3.79 mmol) in ethanol (4 mL), hydrazine hydrate (3.79 g, 75 mmol) wasadded at rt and stirred at 90° C. for 3 h. The completion of thereaction was monitored by TLC. The reaction mixture was concentratedunder reduced pressure and the resulting crude product was dissolved inEtOAc, washed with water and dried over anhydrous Na₂SO₄. Afterevaporation of the solvents, the crude product was purified by flashchromatography to afford the title compound (colorless oil). ¹H NMR (400MHz, DMSO-d₆): δ 8.88 (s, 1H), 6.83-6.81 (m, 2H), 6.73-6.71 (m, 1H),5.98 (s, 2H), 4.12 (m, 2H), 2.93-2.91 (m, 1H), 2.76-2.73 (m, 1H), 1.94(m, 1H), 1.87-1.83 (m, 1H), 1.74 (m, 1H), 1.57-1.48 (m, 4H), 1.24-1.22(d, J=6.5 Hz, 3H). LCMS: (Method A) 292.0 (M+H), Rt. 1.71 min, 96.0%(Max).

Step 3:2-(1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidin-4-yl)-5-methyl-1,3,4-oxadiazole

A solution of1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carbohydrazide (0.18g, 0.62 mmol) in triethyl ortho acetate (1.8 mL) was stirred at 110° C.for 16 h. The reaction mixture was concentrated under reduced pressure.The resulting crude product was dissolved in EtOAc, washed with waterand dried over anhydrous Na₂SO₄. After evaporation of the solvents, thecrude product was purified by flash chromatography to afford the titlecompound (pale brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ 6.86 (s, 1H),6.82 (d, J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 5.97 (m, 2H), 3.42-3.39(m, 1H), 2.90-2.88 (m, 1H), 2.83-2.75 (m, 2H), 2.43 (s, 3H), 2.06-1.86(m, 4H), 1.72-1.59 (m, 2H), 1.25 (d, J=6.8 Hz, 3H). LCMS: (Method A)316.0 (M+H), Rt. 2.10 min, 95.5% (Max). HPLC: (Method A) Rt. 2.10 min,96.9% (Max).

Example 31-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(4-methyl-1H-pyrazol-1-yl)piperidine

Step 1: tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate

To a stirred solution of 1-boc-4-hydroxy piperidine (6.0 g, 29.8 mmol)in dry DCM (100 mL), TEA (8.48 g, 89.5 mmol) and mesyl chloride (5.12 g,44.78 mmol) were added slowly at 0° C. The reaction mixture was stirredat rt for 1 h. It was concentrated under vacuum and the resulting crudeproduct was dissolved in DCM. The resulting solution was washed withbrine, water, dried over anhydrous Na₂SO₄ and concentrated under vacuumto afford the title compound. Yield: 99% (8.32 g, off white solid).LCMS: (Method A) 180.2 (M+H), Rt. 3.79 min, 99.2% (Max).

Step 2: tert-Butyl 4-(4-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-((methylsulfonyl)oxy)piperidine-1-carboxylate (6.8 g, 24 mmol) in dryDMF (80 mL), Cs₂CO₃ (23.45 g, 72 mmol) and 4-methyl pyrazole (2 g, 24mmol) were added and the reaction mixture was stirred at 80° C. for 4 h.The completion of the reaction was monitored by TLC. The reactionmixture was concentrated under vacuum and resulting crude product wasdissolved in DCM. The resulting solution washed with brine, water, driedover anhydrous Na₂SO₄ and concentrated under vacuum to afford the titlecompound (colorless oil). LCMS: (Method A) 166.3 (Boc elimination mass),Rt. 3.92 min, 96.3% (Max).

Step 3: 4-(4-Methyl-1H-pyrazol-1-yl)piperidine hydrochloride

To a stirred solution of tert-butyl4-(4-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.81 g, 3.06 mmol)in dry dioxane (2 mL), HCl in dioxane (10 mL) was added and the reactionmixture was stirred at rt for 2 h. The reaction mixture was concentratedunder vacuum and the crude product was washed with diethyl ether toafford the title compound. Yield: 82% (0.61 g, white oil). LCMS: (MethodA) 166.3 (M+H), Rt. 1.41 min, 95.2% (Max).

Step 4:1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(4-methyl-1H-pyrazol-1-yl)piperidine

The title compound was synthesized by following general procedure D,using 4-(4-methyl-1H-pyrazol-1-yl)piperidine hydrochloride andIntermediate 1. The crude product was purified by flash chromatography,affording the title compound (brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ7.29 (s, 1H), 7.20 (s, 1H), 6.89 (s, 1H), 6.76 (s, 1H), 5.95 (m, 2H),4.06-4.00 (m, 1H), 3.43-3.42 (m, 1H), 3.16-3.14 (m, 1H), 2.97-2.94 (m,1H), 2.15-2.07 (m, 2H), 2.04-2.00 (m, 4H), 1.99-1.92 (m, 3H), 1.37 (d,J=6.8 Hz, 3H). LCMS: (Method A) 314.0 (M+H), Rt. 2.76 min, 93.6% (Max).HPLC: (Method A) Rt 2.78 min, 97.0% (Max).

Example 45-(1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperidin-4-yl)-3-methyl-1,2,4-oxadiazole

Step 1: Ethyl1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxylate

The title compound was synthesized by following general procedure D,using 4-piperidine carboxylic acid ester (25 g, 159 mmol) andIntermediate 1 (49.87 g, 271 mmol). The crude product was purified byflash chromatography, affording the title compound (pale brown liquid).LCMS: (Method A) 306.0 (M+H), Rt. 2.71 min, 29.4% (Max).

Step 2: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxylicacid

To a stirred solution of ethyl1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxylate (1.0 g,3.2 mmol) in dioxane (15 mL), NaOH in water (0.256 g, 6.5 mmol, 1 mLwater) was added at 0° C. and stirred for 20 h at rt. Reaction mixturewas evaporated at 40° C. To the resulting crude product, DCM (30 mL) andwater (15 mL) were added and pH was adjusted to 6.5-7.0 using citricacid. The reaction mixture was extracted with 10% MeOH in DCM (30 mL)and evaporated under reduced pressure to afford the title compound.(pale brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ 7.04-6.72 (m, 3H),5.99-5.95 (m, 2H), 5.08-5.06 (m, 1H), 4.64-4.50 (m, 1H), 2.15-2.08 (m,4H), 1.90-1.50 (m, 2H), 1.46-1.44 (m, 2H), 1.35 (d, J=7.6 Hz, 3H). LCMS:(Method B) 278.0 (M+H), Rt. 2.721 min, 70.13% (Max).

Step 3:5-(1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperidin-4-yl)-3-methyl-1,2,4-oxadiazole

To a stirred solution of1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxylic acid (290mg, 1.05 mmol) in ACN (5 mL), HOBt (163 mg, 1.21 mmol) and EDC.HCl (241mg, 1.26 mmol) were added at rt and stirred for 30 min. ThenN′-hydroxyacetimidamide was added and stirred for overnight at rt. Thereaction mixture was concentrated under vacuum and the resulting residuewas dissolved in EtOAc (50 mL). The EtOAc layer was washed with water(10 mL), brine solution (10 mL), dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude product was purified by preparativeHPLC (Method PB) to afford the title compound (pale brown oil). ¹H NMR(400 MHz, CDCl₃): δ 6.87 (s, 1H), 6.75 (s, 2H), 5.95 (m, 2H), 3.40-3.38(m, 1H), 3.07-3.02 (m, 1H), 2.90-2.85 (m, 2H), 2.38 (s, 3H), 2.13-1.85(m, 6H), 1.35 (d, J=6.4 Hz, 3H). LCMS: (Method A) 316.2 (M+H), Rt. 2.401min, 97.43% (Max). HPLC: (Method A) Rt. 2.452 min, 97.90% (Max).

Example 52-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-phenylthiazole

Step 1: tert-butyl 4-carbamothioylpiperazine-1-carboxylate

To a solution of 1-boc piperazine (5.0 g, 26.88 mmol) in dry THF (50mL), 1,1-thio carbonylimidazole (5.48 g, 29.56 mmol) was added at roomtemperature and stirred for 2 h. The reaction mixture was heated at 50°C. for 1 h. It was cooled down to 0° C. and methanolic ammonia solution(50 mL, 7 N) was added. The mixture was stirred at 60° C. for 20 h. Itwas then diluted with water and extracted with EtOAc. The organic layerwas dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crudeproduct was purified by flash chromatography to give the title compound.Yield: 92% (4.0 g, white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.2 (m,2H), 3.16-3.14 (m, 2H), 2.49-2.48 (m, 6H), 1.30 (s, 9H). LCMS: (MethodA) 246.2 (M+H), Rt. 2.93 min, 95.3% (Max).

Step 2: tert-Butyl 4-(4-phenylthiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (0.5 g, 2.08 mmol) in dioxane(10 mL), triethyl amine (0.22 mL, 2.6 mmol) and2-bromo-1-phenylethan-1-one (0.52 g, 2.6 mmol) were added at rt. Theresulting mixture was stirred at 90° C. for 20 h. The completion of thereaction was monitored by TLC. It was diluted with water and extractedwith EtOAc. The organic layer was separated, dried over anhydrousNa₂SO₄, concentrated under vacuum. The resulting crude product was takenas such for the next step. Yield: 86% (0.5 g, colorless liquid).

Step 3: 4-Phenyl-2-(piperazin-1-yl)thiazole hydrochloride

To a stirred solution of tert-butyl4-(4-phenylthiazol-2-yl)piperazine-1-carboxylate (0.5 g) in dry dioxane(2 mL), HCl in dioxane (10 mL, 4 N) was added at room temperature andstirred for 3 h at same temperature. The reaction mixture wasconcentrated under reduced pressure and the resulting crude product wassuspended in diethyl ether (10 mL). It was filtered and dried undervacuum to afford the title compound. Yield: 75% (350 mg, yellow solid).LCMS: (Method A) 246.2 (M+H), Rt. 2.85 min, 71.5% (Max).

Step 4:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-phenylthiazole

The title compound was synthesized by following general procedure E,using 4-phenyl-2-(piperazin-1-yl)thiazole hydrochloride (0.2 g, 0.8mmol) and Intermediate 1 (0.3 g, 1.6 mmol). The reaction mixture wasstirred at rt for 16 h. The crude product was purified by flashchromatography, affording the title compound (yellow solid). ¹H NMR (400MHz, DMSO-d₆): δ 7.84-7.82 (m, 2H), 7.40-7.36 (m, 3H), 7.30-7.26 (m,1H), 7.14-6.99 (m, 3H), 6.06 (s, 2H), 4.61-4.48 (m, 1H), 4.18-3.98 (m,2H), 3.43- 3.33 (m, 2H) 3.12-2.98 (m, 2H), 2.59-2.49 (m, 2H), 1.63(br.s, 3H). LCMS: (Method A) 394.0 (M+H), Rt. 3.87 min, 98.3% (Max).HPLC: (Method A) Rt. 3.89 min, 99.3% (Max).

Example 62-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(4-methoxyphenyl)thiazole

Step 1: tert-butyl4-(4-(4-methoxyphenyl)thiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 1.0 g, 4.0 mmol) in dioxane (20 mL), triethyl amine(0.6 mL, 8.3 mmol) and 2-bromo-1-(4-methoxyphenyl)ethan-1-one (1.2 g,5.3 mmol) was added at rt and stirred at 90° C. for 20 h. The completionof the reaction was monitored by TLC. The reaction mixture was dilutedwith water (10 mL) and extracted with EtOAc (2×25 mL). The organic layerwas separated, dried over anhydrous Na₂SO₄. After evaporation of thesolvents, the resulting crude product was taken as such for the nextstep. Yield: 53% (0.8 g, pale yellow liquid).

Step 2: 4-(4-Methoxyphenyl)-2-(piperazin-1-yl)thiazole hydrochloride

To a stirred solution of tert-butyl4-(4-(4-methoxyphenyl)thiazol-2-yl)piperazine-1-carboxylate (0.8 g) indry dioxane (5 mL), HCl in dioxane (4 M, 10 mL) was added at rt andstirred for 3 h. The reaction mixture was concentrated under vacuum. Theresulting crude product was triturated in diethyl ether (10 mL),filtrated and dried under vacuum to afford the title compound. Yield:68% (400 mg, yellow solid). LCMS: (Method A) 276.0 (M+H), Rt. 2.82 min,69.9% (Max).

Step 3:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(4-methoxyphenyl)thiazole

The title compound was synthesized by following general procedure E,using 4-(4-methoxyphenyl)-2-(piperazin-1-yl)thiazole hydrochloride (0.5g, 2.7 mmol) and Intermediate 1 (0.9 g, 5.4 mmol). The reaction mixturewas stirred at rt for 16 h. The crude product was purified by flashchromatography, affording the title compound (pale yellow solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.76 (d, J=8.4 Hz, 2H), 7.07 (s, 1H), 6.94-6.91(m, 3H), 6.86-6.84 (m, 1H), 6.78-6.76 (m, 1H), 5.99 (m, 2H), 3.76 (s,3H), 3.43-3.42 (m, 5H), 2.50 (m, 2H) 2.42-2.41 (m, 2H), 1.30 (d, J=6.8Hz, 3H). LCMS: (Method A) 424.0 (M+H), Rt. 3.86 min, 98.7% (Max). HPLC:(Method A) Rt. 3.85 min, 99.3% (Max).

Example 72-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole

To a stirred solution of Intermediate 2 (0.1 g, 0.37 mmol) in dry DMSO(5 mL), K₂CO₃ (0.15 g, 11.11 mmol) and 2-bromo thiazole (0.066 g, 0.407mmol) were added. The reaction mixture was heated in a microwave at 150°C. for 3 h. The reaction mixture was cooled and concentrated undervacuum. The resulting crude product was purified by MD Autoprep (MethodB) to afford the title compound (off white solid). ¹H NMR (400 MHz,CDCl₃): δ 7.20 (d, J=4.0 Hz, 1H), 6.90 (s, 1H), 6.77 (s, 2H), 6.57 (s,1H), 5.97 (s, 2H), 3.48 (s, 4H), 3.36 (s, 1H), 2.60-2.53 (m, 4H), 1.37(s, 3H). LCMS: (Method A) 318.0 (M+H), Rt. 2.04 min, 94.4% (Max). HPLC:(Method A) Rt. 2.04 min, 98.6% (Max).

Example 8-5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-iodopyrimidine

To a stirred solution of Intermediate 2 (0.14 g, 0.51 mmol) in i-propylalcohol (5 mL), TEA (0.22 g, 2.20 mmol) and 2-iodo-5-chloro-pyrimidine(0.1 g, 0.415 mmol) were added and the reaction mixture was heated in amicrowave at 140° C. for 40 min. The reaction mixture was cooled down tort and concentrated under vacuum. The resulting crude product waspurified by flash chromatography to afford the title compound. Yield:60% (83.46 mg, pale brown oil). ¹H NMR (400 MHz, CDCl₃): δ 8.47 (s, 2H),6.89 (d, J=1.6 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H),5.99 (s, 2H), 3.66-3.64 (m, 4H), 3.37-3.35 (m, 1H), 2.44-2.38 (m, 2H)2.35-2.30 (m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 439.0 (M+H),Rt. 3.40 min, 98.3% (Max). HPLC: (Method A) Rt. 3.43 min, 98.6% (Max).

Example 92-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylpyrimidine

To a stirred solution of Intermediate 2 (0.1 g, 0.37 mmol) in dry DMF (5mL), DIPEA (0.22 g, 1.7 mmol) and 2-chloro-4-methyl pyrimidine (0.109 g,0.8 mmol) were added at rt and the reaction mixture was stirred at 120°C. for 12 h. It was cooled down to rt and concentrated under vacuum. Theresulting crude product was purified by flash chromatography to affordthe title compound (brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.17 (d,J=4.8 Hz, 1H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76-6.74 (m, 1H),6.48 (d, J=4.8 Hz, 1H), 5.99 (m, 2H), 3.70-3.66 (m, 4H), 3.40-3.34 (m,1H), 2.43-2.39 (m, 2H), 2.34-2.31 (m, 2H) 2.24 (s, 3H), 1.28 (d, J=6.4Hz, 3H). LCMS: (Method A) 327.0 (M+H), Rt. 2.57 min, 98.1% (Max). HPLC:(Method A) Rt. 2.59 min, 98.6% (Max).

Example 101-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-(pyridin-2-yl)piperazine

The title compound was synthesized by following general procedure D,using 1-pyridyl-2-piperazine (0.2 g, 1.3 mmol) and Intermediate 1 (0.3g, 1.63 mmol). The resulting crude product was purified by silicagelcolumn, affording the title compound (colorless oil). ¹H NMR (400 MHz,DMSO-d₆): δ 8.07 (dd, J=2.0, 4.8 Hz, 1H), 7.51-7.46 (m, 1H), 6.88 (s,1H), 6.84-6.82 (m, 1H), 6.76-6.74 (m, 2H), 6.61-6.58 (m, 1H), 5.98 (m,2H), 3.43-3.40 (m, 4H), 3.34-3.33 (m, 1H), 2.47-2.44 (m, 2H), 2.39-2.35(m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 312.0 (M+H), Rt. 1.83min, 98.0% (Max). HPLC: (Method A) Rt. 1.82 min, 98.4% (Max).

Example 112-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine

The title compound was synthesized by following general procedure D,using 2-(piperazin-1-yl)pyrimidine (0.2 g, 1.21 mmol) and Intermediate 1(0.366 g, 1.82 mmol). The resulting crude product was purified by MDAutoprep (Method B), affording the title compound (colourless oil). ¹HNMR (400 MHz, MeOH-d₄): δ 8.36 (d, J=4.8 Hz, 2H), 6.96 (s, 1H),6.90-6.84 (m, 2H), 6.66 (t, J=4.8 Hz, 1H), 5.99 (s, 2H), 3.92-3.90 (m,4H), 3.33 (m, 1H), 2.83 (m, 4H), 1.59 (d, J=6.0 Hz, 3H). LCMS: (MethodA) 313.2 (M+H), Rt. 2.45 min, 99.4% (Max). HPLC: (Method A) Rt. 2.44min, 99.8% (Max).

As can be seen from the following comparison, the compound of Example 11exhibits a highly increased OGA inhibitor activity as compared to thesimilar compound of Example 1 of U.S. Pat. No. 3,299,067, and is thussignificantly more effective than said compound of U.S. Pat. No.3,299,067 in the indications mentioned in this specification:

U.S. Pat. No. 3,299,067 (Example 1)

OGA IC₅₀ = 998 nM Present Invention (Example 11)

OGA IC₅₀ = 125 nM

Example 122-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-isopropylthiazole

Step 1: t-Butyl 4-(4-isopropylthiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 1.2 g, 4.01 mmol) in THF (10 mL), triethyl amine (0.5mL, 5.3 mmol) and 1-bromo-3-methylbutan-2-one (1.0 mL, 5.3 mmol) wereadded at rt. The resulting mixture was stirred for 16 h at 90° C. Thecompletion of the reaction was monitored by TLC. The reaction mixturewas quenched with water and extracted with EtOAc. The organic layer wasdried over anhydrous Na₂SO₄, concentrated under vacuum and the resultingcrude product was taken as such for next step. Yield: 80% (0.8 g, paleyellow oil). LCMS: (Method A) 312.0 (M+H), Rt. 3.24 min, 95.2% (Max).

Step 2: 4-Isopropyl-2-(piperazin-1-yl)thiazole hydrochloride

To a stirred solution of tert-butyl4-(4-isopropylthiazol-2-yl)piperazine-1-carboxylate (0.8 g, 2.4 mmol) indry dioxane (2 mL), HCl in dioxane (4 N, 10 mL) was added at rt andstirred for 2 h at same temperature. The reaction mixture wasconcentrated under vacuum and the crude product was washed with diethylether to afford the title compound. Yield: 93% (1.2 g, pale yellow oil).

Step 3:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-isopropylthiazole

The title compound was synthesized by following general procedure D,using 4-isopropyl-2-(piperazin-1-yl)thiazole hydrochloride (0.57 g, 2.3mmol) and Intermediate 1 (0.5 g, 2.3 mmol). The resulting crude productwas purified by MD Autoprep (Method C), affording the title compound(pale yellow oil). ¹H NMR (400 MHz, DMSO-d₆): δ 6.89 (s, 1H), 6.84 (d,J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.33 (s, 1H), 5.98 (m, 2H),3.41-3.11 (m, 5H), 2.74-2.72 (m, 1H), 2.46-2.38 (m, 4H), 1.27 (d, J=6.8Hz, 3H), 1.15 (d, J=6.8 Hz, 3H). LCMS: (Method A) 360.0 (M+H), Rt. 2.71min, 94.5% (Max). HPLC: (Method A) Rt. 2.69 min, 98.8% (Max).

Example 132-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(trifluoromethyl)thiazole

Step 1: tert-Butyl4-(4-(trifluoromethyl)thiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 2 g, 13.75 mmol) in dioxane (20 mL), triethyl amine(1.7 mL, 12.24 mmol) and 1-bromo-3,3,3-trifluoro acetone (3.2 g, 16.5mmol) were added and stirred at 90° C. for 3 h. The completion of thereaction was monitored by TLC. The reaction mixture was quenched withwater (10 mL) and extracted with ethyl acetate (2×25 mL). The organiclayer was separated, dried over anhydrous Na₂SO₄, concentrated undervacuum and was used as such for next step. Yield: 75% (1.0 g, whitesolid). ¹H NMR (300 MHz, DMSO-d₆): δ 7.57 (s, 1H), 3.42 (m, 8H), 1.40(s, 9H). LCMS: (Method A) 338.0 (M+H), Rt. 5.37 min, 99.0% (Max).

Step 2: 2-(Piperazin-1-yl)-4-(trifluoromethyl)thiazole hydrochloride

To a stirred solution of tert-butyl4-(4-(trifluoromethyl)thiazol-2-yl)piperazine-1-carboxylate (1.0 g, 2.93mmol) in dry dioxane, HCl in dioxane (4 N, 15 mL) was added and thereaction mixture was stirred at rt for 1 h. The reaction mixture wasconcentrated under vacuum and the resulting crude product was trituratedin diethyl ether, filtrated and dried under vacuum to afford the titlecompound. Yield: 99% (700 mg, white solid). ¹H NMR (400 MHz, DMSO-d₆): δ9.22 (br. s, 2H), 7.66 (s, 1H), 3.68-3.64 (m, 4H), 3.21 (m, 4H). LCMS:(Method A) 238.0 (M+H), Rt. 2.33 min, 99.7% (Max).

Step 3:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(trifluoromethyl)thiazole

To a stirred solution of 2-(piperazin-1-yl)-4-(trifluoromethyl)thiazolehydrochloride (0.26 g, 1.07 mmol) in dry DMF (3 mL), Intermediate 1(0.19 g, 1.07 mmol) and triethyl amine (0.272 g, 2.69 mmol) were addedand the reaction mixture was stirred at 80° C. for 16 h. The reactionmixture was concentrated, the crude product was diluted with ethylacetate (10 mL) and the organic layer was washed with brine (10 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated to afford the title compound (colorless oil). ¹H NMR (400MHz, DMSO-d₆): δ 6.96 (s, 1H), 6.88 (s, 1H), 6.76-7.75 (m, 2H), 5.91 (s,2H), 3.55-3.45 (m, 4H), 3.38 (q, J=6.4 Hz, 1H), 2.62-2.49 (m, 4H),2.56-2.51 (m, 4H), 1.36 (d, J=6.4 Hz, 3H). LCMS: (Method A) 386.0 (M+H),Rt. 3.55 min, 97.4% (Max). HPLC: (Method A) Rt. 3.54 min, 98.7% (Max).

Example 141-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-methylpyridin-2-yl)piperazine

The title compound was synthesized according the general procedure D,using Intermediate 2 and 2-fluoro-5-methyl pyridine. The crude productwas purified by flash chromatography to afford the title compound (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.92 (s, 1H), 7.36-7.33 (m,1H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.70(d, J=8.4 Hz, 1H), 5.99 (m, 2H), 3.37-3.35 (m, 5H), 2.47-2.44 (m, 2H),2.38-2.36 (m, 2H), 2.12 (s, 3H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (MethodA) 326.2 (M+H), Rt. 1.96 min, 97.6% (Max). HPLC: (Method A) Rt. 1.96min, 98.1% (Max).

Example 15(R)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylthiazoleor(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylthiazole

The two enantiomers of Example A were separated by chiral preparativeHPLC (Method PE). The first eluting compound has Rt. 5.76 min (Method C)(colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 6.89 (s, 1H), 6.84 (d,J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.35 (s, 1H), 5.99-5.98 (m, 2H),3.40-3.36 (m, 1H), 3.32-3.29 (m, 4H), 2.47-2.44 (m, 2H), 2.41-2.37 (m,2H), 2.11 (s, 3H), 1.26 (d, J=6.4 Hz, 3H). LCMS: (Method A) 332.0 (M+H),Rt. 2.06 min, 96.3% (Max). HPLC: (Method A) Rt 2.05 min, 99.5% (Max),99.4% (254 nm). HPLC chiral purity: (Method C) Rt. 5.76 min, 100% (Max).Example 15 is the second eluting compound with Rt. 7.44 min (Method C)(colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 6.89 (s, 1H), 6.84 (d,J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.35 (s, 1H), 5.99 (s, 2H),3.42-3.37 (m, 1H), 3.32-3.30 (m, 4H), 2.47-2.44 (m, 2H), 2.40-2.36 (m,2H), 2.11 (s, 3H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 332.0 (M+H),Rt. 2.04 min, 99.2% (Max). HPLC: (Method A) Rt. 2.05 min, 99.2% (Max).HPLC chiral purity: (Method C) Rt. 7.44 min, 99.83% (Max).

Example 162-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(tert-butyl)thiazole

Step 1: tert-butyl4-(4-(tert-butyl)thiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 1.3 g, 5.3 mmol) in dioxane (10 mL), TEA (1 mL, 7mmol) and 1-bromo-3,3-dimethylbutan-2-one (0.94 mL, 6.8 mmol) were addedat rt and stirred for 16 h at 90° C. The completion of the reaction wasmonitored by TLC. The reaction mixture was quenched with water andextracted with EtOAc. The organic layer was dried over anhydrous Na₂SO₄,concentrated under vacuum and the resulting crude product was taken assuch for next step without further purification. Yield: 88% (1.5 g,black liquid). LCMS: (Method A) 326.2 (M+H), Rt. 3.75 min, 60.4% (Max).

Step 2: 4-(tert-Butyl)-2-(piperazin-1-yl)thiazole hydrochloride

To a stirred solution of tert-butyl4-(4-(tert-butyl)thiazol-2-yl)piperazine-1-carboxylate (1.5 g, 4.61mmol) in dry dioxane (2 mL), HCl in dioxane (4 N, 10 mL) was added andthe reaction mixture was stirred at rt for 2 h. The reaction mixture wasconcentrated under vacuum and the resulting crude product was trituratedin diethyl ether (100 mL), filtered and dried under vacuum to afford thetitle compound. Yield: 63% (1.02 g, black solid).

Step 3:2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(tert-butyl)thiazole

The title compound was synthesized following the general procedure D,using 4-(tert-butyl)-2-(piperazin-1-yl)thiazole hydrochloride (0.732 g,2.8 mmol) and Intermediate 1 (0.28 g, 2.8 mmol) and the crude productwas purified by flash chromatography (pale yellow oil). ¹H NMR (400 MHz,DMSO-d₆): δ 6.89 (s, 1H), 6.85 (d, J=7.6 Hz), 6.76 (d, J=7.6 Hz, 1H),6.33 (s, 1H), 5.99 (m, 2H), 3.40 (m, 1H), 3.37-3.30 (m, 4H), 2.49-2.46(m, 2H), 2.43-2.40 (m, 2H), 1.28 (d, J=6.8 Hz, 3H), 1.19 (s, 9H). LCMS:(Method A) 374.0 (M+H), Rt. 3.40 min, 98.6% (Max). HPLC: (Method A) Rt.3.39 min, 99.7% (Max).

Example 17 Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylate

Step 1: Ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-4-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 3.0 g, 12 mmol) in dioxane (10 mL), TEA (2.6 mL, 16mmol) and 3-bromo-ethyl pyruvate (2.1 mL, 16 mmol) were added at rt andthe mixture was stirred at 90° C. for 16 h. The completion of thereaction was monitored by TLC. The reaction mixture was quenched withwater and extracted with EtOAc. The organic layer was dried overanhydrous Na₂SO₄, concentrated under vacuum and the resulting crudeproduct was taken as such for next step. Yield: 95% (4 g, black solid).

Step 2: Ethyl 2-(piperazin-1-yl)thiazole-4-carboxylate hydrochloride

To a stirred solution of ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-4-carboxylate (4.0 g,11.73 mmol) in dry dioxane (2 mL), HCl in dioxane (4 N, 10 mL) was addedat rt and stirred for 2 h. The reaction mixture was concentrated undervacuum and the resulting crude product was triturated in diethyl ether(25 mL), filtered and dried under vacuum to afford the title compound.Yield: 90% (3.2 g, black solid). LCMS: (Method A) 242.0 (M+H), Rt. 1.88min, 90.7% (Max).

Step 3: Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylate

The title compound was synthesized following the general procedure D,using ethyl 2-(piperazin-1-yl)thiazole-4-carboxylate hydrochloride andIntermediate 1 and the crude product was purified by flashchromatography followed by MD Autoprep (Method B) (yellow solid). ¹HNMR(400 MHz, DMSO-d₆): δ 7.66 (d, J=2.0 Hz, 1H), 6.88 (s, 1H), 6.84 (d,J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 4.21-4.20 (m, 2H),3.38-3.32 (m, 5H), 2.49-2.40 (m, 4H), 1.26-1.23 (m, 6H). LCMS: (MethodA) 390.0 (M+H), Rt. 2.99 min, 97.8% (Max). HPLC: (Method A) Rt. 2.95min, 98.9% (Max).

Example 182-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylicacid

To a stirred solution of Example 17 (0.2 g) in dry THF (10 mL), 5% NaOHin water (5 mL) was added slowly at rt and the mixture was stirred for16 h at same temperature. It was then concentrated under vacuum,neutralised to pH=6 with 2N HCl and extracted with DCM (20 mL). Theorganic layer was washed with brine (10 mL), water (10 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography followed by MD Autoprep(Method B) to afford the title compound (off white solid). ¹H NMR (400MHz, DMSO-d₆): δ 7.58 (s, 1H), 6.90 (s, 1H), 6.88 (d, J=8.0 Hz, 1H),6.76 (d, J=8.0 Hz, 1H), 6.00-5.99 (m, 2H), 3.35-3.36 (m, 5H), 2.51-2.49(m, 2H), 2.44-2.40 (m, 2H), 1.29-1.27 (d, J=6.8 Hz, 3H). LCMS: (MethodA) 362.0 (M+H), Rt. 2.29 min, 95.5% (Max). HPLC: (Method A) Rt. 2.30min, 95.9% (Max).

Example 192-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-ethylthiazole

Step 1: t-Butyl 4-(4-ethylthiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 2.0 g, 8.16 mmol) in dioxane (20 mL), TEA (1.7 mL,10.6 mmol) and 1-bromobutan-2-one (1.2 mL, 10 mmol) were added andstirred at 80° C. for 16 h. The completion of the reaction was monitoredby TLC. The reaction mixture was quenched with water (10 mL) andextracted with EtOAc (2×25 mL). The organic layer was separated, driedover anhydrous Na₂SO₄, concentrated under vacuum. The resulting productwas taken as such for next step. Yield: 86% (2.1 g, pale yellow solid).LCMS: (Method A) 298.0 (M+H), Rt. 2.94 min, 93.1% (Max).

Step 2: 4-Ethyl-2-(piperazin-1-yl)thiazole hydrochloride

To a stirred solution of tert-butyl4-(4-ethylthiazol-2-yl)piperazine-1-carboxylate (1.9 g, 6.3 mmol) in drydioxane (2 mL), HCl in dioxane (4 N, 10 mL) was added and the reactionmixture was stirred at rt for 2 h. The reaction mixture was concentratedunder vacuum and the crude product was triturated in diethyl ether (15mL), filtered and dried under vacuum to afford the title compound.Yield: 53% (0.8 g, black solid).

Step 3:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-ethylthiazole

The title compound was synthesized following the general procedure D,using 4-ethyl-2-(piperazin-1-yl)thiazole hydrochloride (1.1 g, 4.7 mmol)and Intermediate 1 (0.9 g, 4.7 mmol). The crude product was purified byflash chromatography (pale yellow oil). ¹H NMR (400 MHz, DMSO-d₆): δ6.89 (d, J=1.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H),6.35 (s, 1H), 5.98 (m, 2H), 3.40-3.37 (m, 1H), 3.37-3.30 (m, 4H),2.51-2.38 (m, 6H), 1.28 (d, J=6.8 Hz, 3H), 1.23 (t, J=7.6 Hz, 3H). LCMS:(Method A) 346.0 (M+H), Rt. 2.31 min, 98.0% (Max). HPLC: (Method A) Rt.2.34 min, 99.4% (Max).

Example 201-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-(6-chloropyridin-3-yl)piperazine

The title compound was synthesized following the general procedure D,using Intermediate 1 and 1-(5-chloro-2-pyridyl) piperazine. The crudeproduct was purified by flash chromatography (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.07 (d, J=2.4 Hz, 1H), 7.57-7.54 (m, 1H),6.88-6.74 (m, 4H), 5.98 (m, 2H), 3.42 (q, J=6.4 Hz, 1H), 2.46-2.43 (m,2H), 2.37-2.34 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 346.0(M+H), Rt. 3.27 min, 98.7% (Max). HPLC: (Method A) Rt 3.25 min, 99.2%(Max).

Example 211-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-(6-methylpyridin-2-yl)piperazine

To a stirred solution of Intermediate 2 (0.12 g, 0.5 mmol) in dry DMF (2mL), 2-fluoro-6-methyl pyridine (0.11 g, 0.99 mmol) and DIPEA (0.26 g,2.4 mmol) were added at rt and the reaction mixture was stirred at 120°C. for 16 h. The reaction mixture was cooled to rt and concentratedunder vacuum. The resulting crude product was purified by flashchromatography followed by preparative HPLC (Method PA) to afford thetitle compound (brown liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.40-7.36(m, 1H), 6.90 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H),6.55-6.46 (m, 2H), 5.98 (s, 2H), 3.410-3.415 (m, 5H), 2.38-2.37 (m, 4H),2.28-2.30 (m, 3H), 1.29 (d, J=7.2 Hz, 3H). LCMS: (Method A) 326.2 (M+H),Rt. 1.89 min, 94.9% (Max). HPLC: (Method A) Rt 1.91 min, 96.6% (Max).

Example 222-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-4-amine

The title compound was synthesized by following procedure D, usingIntermediate 2 (0.228 g, 0.85 mmol) and 4-amino-2-chloro pyrimidine (0.1g, 0.77 mmol). The crude product was purified by flash chromatographyfollowed by MD Autoprep (Method B) (white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.70 (d, J=5.2 Hz, 1H), 6.88 (s, 1H), 6.83 (d, J=8.0 Hz,1H), 6.75 (d, J=7.6 Hz, 1H), 6.36 (s, 2H), 5.98 (m, 2H), 5.69 (d, J=5.6Hz, 1H), 3.6-3.58 (m, 4H), 3.33-3.32 (m, 1H), 2.38-2.34 (m, 2H),2.31-2.27 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 328.0 (M+H),Rt. 1.85 min, 97.2% (Max). HPLC: (Method A) Rt. 1.84 min, 97.1% (Max).

Example 23N-(2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-4-yl)acetamide

Step 1: N-(2-Chloropyrimidin-4-yl)acetamide

To a stirred solution of 4-amino-2-chloro pyrimidine (0.6 g, 4.65 mmol)in DCM (5 mL), pyridine (1.8 mL) and acetic anhydride (0.71 g, 6.9 mmol)were added at 0° C. and stirred at 75° C. for 6 h. The reaction mixturewas concentrated under vacuum and the resulting crude product wasdissolved in EtOAc (15 mL). The organic layer was washed with water (10mL), brine (10 mL) and dried over anhydrous Na₂SO₄. After concentrationunder vacuum, the crude product was taken as such for next step. Yield:56.9% (0.45 g, pale brown solid). LCMS: (Method A) 172.0 (M+H), Rt. 1.58min, 80.2% (Max).

Step 2:N-(2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-4-yl)acetamide

The title compound was synthesized following procedure D and usingIntermediate 2 (0.25 g, 0.93 mmol) andN-(2-chloropyrimidin-4-yl)acetamide (0.19 g, 1.12 mmol). The crudeproduct was purified by flash chromatography followed by MD Autoprep(Method B) (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 10.30 (s, 1H),8.18 (d, J=5.6 Hz, 1H), 7.21 (d, J=5.6 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H),6.84 (d, J=7.6 Hz, 1H), 6.75 (dd, J=1.6, 8 Hz, 1H), 5.98 (m, 2H),3.68-3.66 (m, 4H), 3.37-3.36 (m, 1H), 2.42-2.38 (m, 2H), 2.35-2.31 (m,2H), 2.07 (s, 3H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 370.0 (M+H),Rt. 2.26 min, 97.5% (Max). HPLC: (Method A) Rt. 2.21 min, 98.9% (Max).

Example 244-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6-chloropyrimidine

To a stirred solution of Intermediate 2 (0.2 g, 0.74 mmol) in DMF (5mL), TEA (0.5 mL, 3.70 mmol) and 4,6-dichloro pyrimidine (0.11 g, 0.74mmol) were added and the resulting mixture was stirred at 120° C. for 2h. It was concentrated under vacuum and the resulting crude product wasdissolved in DCM and washed with water, dried over anhydrous Na₂SO₄, andconcentrated under vacuum. The crude product was purified by flashchromatography to afford the title product (brown oil). ¹H NMR (400 MHz,DMSO-d₆): δ 8.30 (s, 1H), 6.91 (s, 1H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz,1H), 6.75 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 3.55-3.52 (m, 4H), 3.39-3.37(m, 1H), 2.43-2.39 (m, 2H), 2.36-2.32 (m, 2H), 1.27 (d, J=6.8 Hz, 3H).LCMS: (Method A) 347.0 (M+H), Rt. 2.55 min, 98.7% (Max). HPLC: (MethodA) Rt. 2.57 min, 99.7% (Max).

Example 252-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6-chloropyrazine

To a stirred solution of Intermediate 2 (0.2 g, 0.74 mmol) in DMF (5mL), TEA (0.5 mL, 3.70 mmol) and 2,5-dichloro pyrazine (0.11 g, 0.74mmol) was added and stirred at 120° C. for 2 h. The reaction mixture wasconcentrated under vacuum and the resulting crude product was dissolvedin DCM. It was washed with water, dried over anhydrous Na₂SO₄, andconcentrated under vacuum. The crude product was purified by flashchromatography to afford the title compound (brown oil). ¹H NMR (400MHz, DMSO-d₆): δ 8.23 (s, 1H), 7.81 (s, 1H), 6.88 (d, J=1.2 Hz, 1H),6.84 (d, J=8.0 Hz, 1H), 6.74 (dd, J=1.6, 8.0 Hz, 1H), 5.97 (s, 2H),3.54-3.52 (m, 4H), 3.39-3.37 (m, 1H), 2.45-2.44 (m, 2H), 2.39-2.37 (m,2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 347.0 (M+H), Rt. 3.03 min,97.9% (Max). HPLC: (Method A) Rt. 3.05 min, 97.6% (Max).

Example 26(R)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine or(S)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine

The two enantiomers of Example 11 were separated by chiral preparativeHPLC (Method PF). The first eluting compound has Rt. 8.50 min (colorlessoil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.32 (d, J=4.8 Hz, 2H), 6.88 (s, 1H),6.83 (d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.58 (t, J=4.4 Hz, 1H),5.97 (m, 2H), 3.68-3.67 (m, 4H), 3.37-3.35 (m, 1H), 2.49-2.38 (m, 2H),2.35-2.30 (m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 313.0 (M+H),Rt. 2.45 min, 99.5% (Max). HPLC: (Method A) Rt. 2.47 min, 99.5% (Max).HPLC chiral purity: (Method D) Rt. 8.50 min, 100% (Max). Example 26 isthe second eluting compound, with Rt. 13.33 min (colorless oil). ¹H NMR(400 MHz, DMSO-d₆): δ 8.32 (d, J=4.8 Hz, 2H), 6.88 (s, 1H), 6.83 (d,J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.58 (t, J=4.4 Hz, 1H), 5.97 (m,2H), 3.68-3.67 (m, 4H), 3.36-3.33 (m, 1H), 2.49-2.38 (m, 2H), 2.35-2.30(m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 313.0 (M+H), Rt. 2.44min, 99.5% (Max). HPLC: (Method A) Rt. 2.47 min, 99.8% (Max). HPLCchiral purity: (Method D) Rt. 13.33 min, 100% (Max).

Example 27 Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

Step 1: Ethyl 2-bromothiazole-5-carboxylate

To a stirred solution of ethyl-2-amino thiazole-5-carboxylate (10.0 g,46.45 mmol, Combi block) in 48% HBr (75 mL), sodium nitrite (4.80 g,69.68 mmol) in water (50 mL) was added dropwise at 0° C. and thereaction mixture was stirred at 0° C. for 15 min. Copper (I)bromide(6.66 g, 46.45 mmol) in 48% HBr (75 mL) was added dropwise at 0° C. andthe reaction mixture was stirred at rt for 4 h. The reaction mixture wasdiluted with DCM (200 mL) and washed with water (50 mL), brine (50 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography (100% CHCl₃) to afford thetitle compound. Yield: 50.18% (5.5 g, yellow liquid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.16 (s, 1H), 4.38 (q, J=7.16 Hz, 2H), 1.40 (t, J=7.12 Hz,3H). LCMS: (Method A) 235.9 (M+H), Rt. 3.85 min, 98.6% (Max).

Step 2: Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

To a stirred solution of Intermediate 2 (1.5 g, 6.40 mmol) in dry DMF(15 mL), ethyl 2-bromothiazole-5-carboxylate (1.96 g, 8.32 mmol) and TEA(3.5 mL, 25.6 mmol) were added at rt and the reaction mixture wasstirred at 120° C. for overnight. The reaction mixture was cooled to rtand was diluted with EtOAc. The organic layer was washed with brine (10mL), water (10 mL), dried over anhydrous Na₂SO₄ and concentrated undervacuum. The crude product was purified by column chromatography toafford the title compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆):δ 7.83 (s, 1H), 6.89 (s, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz,1H), 5.99 (s, 2H), 4.19 (q, J=6.8 Hz, 2H), 3.50-3.42 (m, 5H), 2.51-2.46(m, 2H), 2.44-2.33 (m, 2H), 1.30-1.22 (m, 6H). LCMS: (Method A) 247.2(M+H), Rt. 3.17 min, 78.6% (Max).

Example 28(2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methanol

The title compound was synthesized following the general procedure Astarting from Example 27. The crude product was purified by flashchromatography followed by MD Autoprep (Method B) (off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 6.96 (s, 1H), 6.89 (s, 1H), 6.84 (d, J=7.6 Hz,1H), 6.75 (d, J=7.6 Hz, 1H), 5.98 (m, 2H), 5.21 (t, J=5.6 Hz, 1H), 4.44(d, J=5.6 Hz, 2H), 3.40-3.37 (m, 1H), 3.34-3.31 (m, 4H), 2.46-2.42 (m,2H), 2.41-2.38 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 348.0(M+H), Rt. 1.91 min, 96.3% (Max). HPLC: (Method A) Rt. 1.89 min, 95.1%(Max).

Example 29(2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-4-yl)methanol

The title compound was synthesized following general procedure A,starting with Example 17 (0.5 g) and the crude product was purified byflash chromatography (pale yellow oil). ¹H NMR (400 MHz, DMSO-d₆): δ6.89 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.75 (dd, J=1.6, 8.0 Hz, 1H), 6.52(s, 1H), 5.99 (m, 2H), 5.11-5.09 (t, J=8.0 Hz, 1H), 4.31 (d, J=8.0 Hz,2H), 3.40-3.34 (m, 5H), 2.51-2.49 (m, 2H), 2.42-2.32 (m, 2H), 1.28 (d,J=6.8 Hz, 3H). LCMS: (Method A) 348.0 (M+H), Rt. 1.98 min, 94.8% (Max).HPLC: (Method A) Rt. 1.99 min, 96.0% (Max).

Example 302-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide

To a stirred solution of Example 18 (0.3 g, 0.5 mmol) in DCM (10 mL),DIPEA (0.6 mL, 2 mmol) and HATU (0.56 g, 1.48 mmol) were added slowly at0° C. The reaction mixture was stirred at 0° C. for 20 min. Methyl aminein THF (0.6 mL, 1.48 mmol) was added and the reaction mixture wasstirred overnight at room temperature. The reaction mixture was dilutedwith EtOAc (10 mL) and washed with water (10 mL) and brine (10 mL). Theorganic layer was dried over anhydrous Na₂SO₄, concentrated undervacuum. The crude product was purified by flash chromatography followedby MD Autoprep (Method B) to afford the title compound (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.96 (d, J=4.8 Hz, 1H), 7.33 (s,1H), 6.89 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.75 (dd, J=1.6, 8.0 Hz, 1H),5.98 (m, 2H), 3.43-3.38 (m, 5H), 2.72 (d, J=4.8 Hz, 3H), 2.41-2.39 (m,4H), 1.27 (d, J=6.4, 3H). LCMS: (Method A) 375.0 (M+H), Rt. 2.34 min,98.2% (Max). HPLC: (Method A) Rt. 2.32 min, 99.0% (Max).

Example 313-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6-chloropyridazine

The title compound was synthesized following general procedure D, usingIntermediate 2 and 3,6-dichloro pyridazine. The crude product waspurified by flash chromatography (off white solid). ¹H NMR (DMSO-d₆): δ7.65 (d, J=9.6 Hz, 1H), 7.46 (d, J=9.6 Hz, 1H), 7.21 (s, 1H), 7.01-6.98(m, 2H), 6.08 (s, 2H), 4.50-4.44 (m, 1H), 4.39-4.36 (m, 1H), 3.80-3.75(m, 1H), 3.45-3.42 (m, 1H), 3.28- 3.25 (m, 1H), 3.18-3.15 (m, 1H),3.11-3.08 (m, 1H), 3.01-2.98 (m, 1H), 2.92-2.86 (m, 1H), 1.67 (d, J=6.8Hz, 3H). LCMS: (Method A) 347.0 (M+H), Rt. 2.55 min, 96.5% (Max). HPLC:(Method A) Rt. 2.58 min, 95.5% (Max).

Example 322-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-isopropylthiazole-4-carboxamide

The title compound was synthesized by following the same procedure asdescribed for Example 30, using Example 18 (0.3 g, 0.9 mmol) andisopropyl amine (0.09 mL, 1.08 mmol) as starting material (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.62 (d, J=8.4 Hz, 1H), 7.35 (s,1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 5.99(m, 2H), 4.04-3.99 (m, 1H), 3.43-3.34 (m, 5H), 2.50-2.42 (m, 4H), 1.29(d, J=6.8 Hz, 3H), 1.14-1.07 (m, 6H). LCMS: (Method A) 403.0 (M+H), Rt.2.90 min, 95.5% (Max). HPLC: (Method A) Rt. 2.91 min, 96.5% (Max).

Example 332-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-cyclohexylthiazole-4-carboxamide

The title compound was synthesized by following the same procedure asdescribed for Example 30, using Example 18 (0.3 g, 0.9 mmol) andcyclohexyl amine (0.12 mL, 1.08 mmol) as starting material (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.60 (d, J=8.4 Hz, 1H), 7.35 (s,1H), 6.90 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 5.99(s, 2H), 3.68-3.67 (m, 1H), 3.42 (br.s, 4H), 2.50-2.42 (m, 4H),1.74-1.70 (m, 4H), 1.59-1.56 (m, 1H), 1.36-1.23 (m, 8H), 1.13-1.09 (m,1H). LCMS: (Method A) 443.0 (M+H), Rt. 3.57 min, 97.9% (Max). HPLC:(Method A) Rt. 3.62 min, 99.3% (Max).

Example 34(R)-2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)pyrimidineor(S)-2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)pyrimidine

The title compound was synthesized by following procedure D, usingIntermediate 3 (2.2 g, 11 mmol) and 1-(2-pyrimidyl) piperazine (1.8 g,11 mmol). The crude product was purified by flash chromatographyfollowed by preparative chiral HPLC (Method PF) to separate the twoenanatiomers. The first eluting compound has Rt. 7.90 min (Method D)(off white solid). ¹H NMR 400 MHz, DMSO-d₆): δ 8.32 (d, J=4.4 Hz, 2H),6.78-6.75 (m, 3H), 6.59 (t, J=9.6 Hz, 1H), 4.21-4.20 (m, 4H), 3.68-3.67(m, 4H), 3.36-3.26 (m, 1H), 2.49-2.39 (m, 2H), 2.34-2.32 (m, 2H), 1.25(d, J=6.4 Hz, 3H). LCMS: (Method A) 327.2 (M+H), Rt. 2.51 min, 98.7%(Max). HPLC: (Method A) Rt. 2.54 min, 99.3% (Max). HPLC chiral purity:(Method D) Rt. 7.90 min, 100.0% (Max). Example 34 corresponds to thesecond eluting compound, with Rt. 13.92 min (Method D) (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.32 (d, J=4.4 Hz, 2H), 6.80-6.75(m, 3H), 6.59 (t, J=9.6 Hz, 1H), 4.21-4.20 (m, 4H), 3.69-3.66 (m, 4H),3.33-3.32 (m, 1H), 2.44-2.38 (m, 2H), 2.36-2.31 (m, 2H), 1.26 (d, J=6.8Hz, 3H). LCMS: (Method A) 327.0 (M+H), Rt. 2.51 min, 99.1% (Max). HPLC:(Method A) Rt. 2.49 min, 99.2% (Max). HPLC chiral purity: (Method D) Rt.13.92 min, 99.88% (Max).

Example 352-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-4-carboxamide

The title compound was synthesized by following the same procedure asdescribed for Example 30, using Example 18 (0.3 g, 0.9 mmol) and ammoniain THF (4.5 mL, 9 mmol, 2 M in THF) as starting material. The crudemixture was purified by flash chromatography (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.39 (br s, 2H), 7.37 (s, 1H), 6.90 (s, 1H), 6.85(d, J=7.6 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 5.99 (br s, 2H), 3.41-3.34(m, 5H), 2.50-2.43 (m, 4H), 1.30 (d, J=6.8 Hz, 3H). LCMS: (Method A)361.0 (M+H), Rt. 2.19 min, 94.8% (Max). HPLC: (Method A) Rt. 2.17 min,98.0% (Max).

Example 365-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-methylthiazole

The title compound was synthesized following general procedure D, using2-bromo-5-methyl thiazole and Intermediate 2. The crude product waspurified by flash chromatography (brown solid). ¹H NMR (DMSO-d₆): δ 6.89(s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.76-6.74 (m,1H), 5.99 (m, 2H), 3.40-3.36 (m, 1H), 3.29-3.26 (m, 4H), 2.46-2.45 (m,2H), 2.42-2.38 (m, 2H), 2.23 (s, 3H), 1.28-1.27 (m, 3H). LCMS: (MethodA) 332.0 (M+H), Rt. 2.13 min, 96.0% (Max). HPLC: (Method A) Rt. 2.11min, 97.4% (Max).

Example 375-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-methylthiazole

The mixture of 5-bromo-2-methyl thiazole (150 mg, 0.84 mmol),Intermediate 2 (200 mg, 0.84 mmol) and TEA (344 mg, 3.4 mmol) in DMF (4mL) was heated at 130° C. for overnight. It was concentrated undervacuum and to the resulting crude product was dissolved in EtOAc (10 mL)and washed with water (10 mL). The organic layer was dried over Na₂SO₄and concentrated. The crude product was purified by flash columnchromatography (brown solid). ¹H NMR (DMSO-d₆): δ 6.90 (s, 1H),6.85-6.78 (m, 3H), 5.95 (br s, 2H), 3.55-3.51 (m, 1H), 3.12-3.11 (m,4H), 2.80-2.65 (m, 4H), 2.54 (s, 3H), 1.44 (d, J=5.6 Hz, 3H). LCMS:(Method A) 332.0 (M+H), Rt. 5.71 min, 97.35% (Max). HPLC: (Method B) Rt.5.64 min, 96.8% (Max).

Example 385-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-chloropyrimidine

The title compound was synthesized following the general procedure D,using Intermediate 2 and 2,5-dichloropyrimidine. The crude product waspurified by flash chromatography (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.38 (s, 2H), 6.88 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.75 (m,J=8.0 Hz, 1H), 5.98 (m, 2H), 3.68-3.65 (m, 4H), 3.38-3.369 (m, 1H),2.44-2.39 (m, 1H), 2.36-2.32 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS:(Method A) 347.0 (M+H), Rt. 3.24 min, 98.3% (Max). HPLC: (Method A) Rt.3.22 min, 99.6% (Max).

Example 392-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methoxypyrimidine

The title compound was synthesized following general procedure D, usingIntermediate 2 and 2-chloro-5-methoxy pyrimidine. The crude product waspurified by flash chromatography (white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.04 (d, J=5.6 Hz, 1H), 6.88-0 (s, 1H), 6.83 (d, J=8.0 Hz,1H), 6.74 (d, J=8.0 Hz, 1H), 6.02 (d, J=5.6 Hz, 1H), 5.98 (br s, 2H),3.79 (s, 3H), 3.72-3.66 (m, 4H), 3.37-3.39 (m, 1H), 2.43-2.39 (m, 2H),2.34-2.30 (m, 2H), 1.28-1.26 (d, J=6.4 Hz, 3H). LCMS: (Method A) 343.0(M+H), Rt. 2.27 min, 99.6% (Max). HPLC: (Method A) Rt. 2.27 min, 99.4%(Max).

Example 404-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-chloropyrimidine

The title compound was synthesized following the general procedure D,using Intermediate 2 and 2,4-dichloropyrimidine. The crude product waspurified by flash chromatography (yellow oil). ¹H NMR (400 MHz,DMSO-d₆): δ 8.04 (d, J=7.6 Hz, 1H), 6.89 (s, 1H), 6.85 (d, J=8.0 Hz,1H), 6.80-6.75 (m, 2H), 5.99 (m, 2H), 3.59 (br.s, 4H), 3.39 (q, J=6.4Hz, 1H), 2.45-2.42 (m, 2H), 2.38-2.33 (m, 2H), 1.29-1.27 (d, J=6.8 Hz,3H). LCMS: (Method A) 347.0 (M+H), Rt. 2.59 min, 96.4% (Max). HPLC:(Method A) Rt. 2.51 min, 98.2% (Max).

Example 415-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-amine

The title compound was synthesized following the general procedure D,using Intermediate 2 and 2-amino-5-bromo-1,3,4-thiadiazole. The crudeproduct was purified by recrystallisation. Yield: 81% (2.0 g, off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.88-6.87 (m, 1H), 6.85-6.83 (m,1H), 6.76-6.73 (m, 1H), 6.47 (s, 2H) 5.99 (s, 2H), 3.40-3.34 (m, 1H),3.19-3.17 (m, 4H), 2.47-2.43 (m, 2H), 2.40-2.36 (m, 2H), 1.27 (d, J=6.4Hz, 3H). LCMS: (Method A) 334.0 (M+H), Rt. 1.84 min, 96.5% (Max). HPLC:(Method A) Rt. 1.83 min, 98.2% (Max).

Example 422-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-4-carboxamide

The title compound was synthesized following the same procedure asdescribed for Example 30, using Example 18 (0.3 g, 0.9 mmol) anddimethyl amine (0.9 mL, 1.8 mmol, 2 M in THF) as starting material (paleyellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.16 (s, 1H), 6.89 (s, 1H),6.85 (d, J=7.6 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (br s, 2H),3.41-3.34 (m, 5H), 3.30 (s, 3H), 2.90 (s, 3H), 2.43-2.42 (m, 4H), 1.28(d, J=6.8 Hz, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 2.41 min, 95.1%(Max). HPLC: (Method A) Rt. 2.38 min, 94.3% (Max).

Example 432-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-isopropylthiazole-5-carboxamide

Step 1:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylicacid

To a stirred solution of Example 27 (0.8 g, 2.05 mmol) in dioxane (24mL), NaOH (2M in water, 3 mL) was added slowly. The reaction mixture wasstirred overnight at room temperature. It was then concentrated undervacuum and neutralized with HCl (1.5 N) up to pH=6 and was extractedwith DCM (25 mL). The organic layer was washed with water (15 mL), brine(15 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford the title compound (off white solid). LCMS: (MethodA) 362.0 (M+H), Rt. 2.30 min, 77.6% (Max).

Step 2:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-isopropylthiazole-5-carboxamide

To a solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylicacid (0.1 g, 0.277 mmol) in dry DCM (2 mL), HATU (0.16 g, 0.41 mmol) wasadded and the resulting mixture was stirred at room temperature for 1 h.Isopropyl amine (0.02 g, 0.36 mmol) and DIPEA (0.14 mL, 0.83 mmol) wereadded at 0° C. and the mixture was stirred overnight at roomtemperature. The reaction was quenched with water (10 mL) and extractedwith EtOAc (25 mL). The organic layer was dried over anhydrous Na₂SO₄and concentrated under vacuum. The resulting crude product was purifiedby MD Autoprep (Method B) to afford the title compound (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.96 (d, J=7.6 Hz, 1H), 7.78 (s,1H), 6.89 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.99(br s, 2H), 3.98-3.96 (m, 1H), 3.42-3.41 (m, 5H), 2.42-2.38 (m, 4H),1.28 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.8 Hz, 6H). LCMS: (Method A) 403(M+H), Rt. 2.72 min, 97.81% (Max). HPLC: (Method A) Rt. 2.70 min, 98.62%(Max).

Example 44N-(5-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of Example 41 (0.06 g, 0.7 mmol),diisopropylethylamine (0.4 mL, 0.32 mmol) in dry DCM (4.0 mL), aceticanhydride (0.96 mL, 1.05 mmol) was added at 0° C. and the resultingmixture was stirred for 5 h at rt. The completion of the reaction wasmonitored by TLC. The reaction mixture was concentrated and the crudeproducts were purified by flash chromatography to afford the titlecompound (colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (m, 1H), δ6.89 (m, 1H), 6.86-6.84 (m, 1H), 6.77-6.75 (m, 1H), 5.99 (m, 2H),3.41-3.40 (m, 5H), 2.51-2.50 (m, 2H), 2.43-2.40 (m, 2H), 2.10 (s, 3H),1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 376.0 (M+H), Rt. 2.512 min,96.77% (Max). HPLC: (Method A) Rt. 2.262 min, 98.69% (Max).

Example 452-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-propylpyrimidin-4-amine

Step 1: 2-chloro-N-propylpyrimidin-4-amine

To a stirred solution of 2,4-dichloro pyrimidine (0.2 g, 1.34 mmol) indry THF (10 mL), TEA (0.54 g, 5.36 mmol) and propyl amine (0.088 g, 1.34mmol) were added and the resulting mixture was stirred at roomtemperature for 10 h. It was diluted with water and extracted withEtOAc. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford the title compound. Yield: 70% (0.18g, colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 7.92-7.85 (m, 2H),6.49-6.41 (m, 1H), 3.21 (t, J=6.4 Hz 2H), 1.56-1.47 (m, 2H), 0.91-0.87(t, J=7.36 Hz, 3H). LCMS: (Method A) 172.0 (M+H), Rt. 2.07 min, 99.5%(Max).

Step 2:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-propylpyrimidin-4-amine

To a stirred solution of Intermediate 2 (0.2 g, 0.9 mmol) in dry DMF(4.0 mL), 2-chloro-N-propylpyrimidin-4-amine (0.18 g, 1.04 mmol) and TEA(0.5 mL, 3.2 mmol) were added at 0° C. The reaction mixture was stirredat 130° C. for overnight. It was then concentrated and the crude productwas purified by flash chromatography to afford the title compound(colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 7.65 (s, 1H), 6.89-6.75(m, 3H), 6.12-5.95 (m, 3H), 5.83 (br. s, 1H), 3.62 (m, 4H), 3.20 (s,3H), 2.51-2.49 (m, 4H), 1.50 (qm, 2H), 1.28-1.24 (m, 3H), 0.88 (t, J=8.0Hz, 3H). LCMS: (Method A) 370.0 (M+H), Rt. 2.604 min, 97.37% (Max).HPLC: (Method A) Rt. 2.54 min, 99.78% (Max).

Example 464-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-2-amine

The title compound was synthesized following the general procedure D,using Intermediate 2 and 2-amino-4-chloropyrimidine. The crude productwas purified by flash chromatography (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.72 (d, 1H, J=6.0 Hz), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz,1H), 6.75 (d, J=8.0 Hz, 1H), 5.98-5.95 (m, 5H), 3.46-3.45 (m, 4H),3.37-3.35 (m, 1H), 2.40-2.37 (m, 2H), 2.33-2.29 (m, 2H), 1.27 (d, J=6.4Hz, 3H). LCMS: (Method A) 328.0 (M+H), Rt. 1.86 min, 97.06% (Max). HPLC:(Method A) Rt. 1.81 min, 97.5% (Max).

Example 472-(4-(1-(Benzo[d](1,3)dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamide

To a stirred solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylicacid (Example 43, Step 1, 0.155 g, 0.4 mmol) and HATU (0.206 g, 1.2mmol) in dry DMF (3 mL), DIPEA (0.1 mL, 0.8 mmol) was added and theresulting mixture was stirred for 30 min at room temperature.Dimethylamine in THF (0.5 mL, 8.4 mmol) was then added at 0° C. Thereaction mixture was stirred overnight at room temperature. Solventswere evaporated and the resulting crude mixture was diluted with EtOAc,washed with water, 10% sodium bicarbonate solution, brine and dried overNa₂SO₄. After evaporation of the solvents, the resulting crude productwas purified by MD Autoprep (Method B) to afford the title compound (offwhite solid). ¹H NMR (400 MHz, CDCl₃): δ 7.47 (s, 1H), 6.87 (s, 1H),6.77-6.76 (m, 2H), 5.96 (s, 2H), 3.52-3.51 (m, 4H), 3.37-3.36 (m, 1H),3.17 (s, 6H), 2.57-2.52 (m, 4H), 2.26 (s, 3H). LCMS: (Method B) 389(M+H), Rt. 5.049 min, 98.02% (Max). HPLC: (Method A) Rt. 2.42 min,98.49% (Max).

Example 482-(4-(1-(Benzo[d](1,3)dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxamide

To a solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylicacid (Example 43, Step 1, 0.15 g, 0.4 mmol) in dry DMF (3 mL), HATU(0.206 g, 1.2 mmol) was added and stirred at room temperature for 20min. Ammonia in THF (5 mL) and DIPEA (0.14 mL, 0.83 mmol) were thenadded at 0° C. The resulting reaction mixture was stirred at roomtemperature overnight. It was concentrated under reduced pressure. EtOAcwas added to the resulting mixture and was washed with water, 10% sodiumbicarbonate solution, brine and dried over Na₂SO₄. After evaporation ofthe solvents, the crude product was purified by MD Autoprep (Method C)to afford the title compound (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.76 (s, 1H), 7.67 (br s, 1H), 7.11 (br s, 1H), 6.89 (s,1H), 6.84 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 5.99 (br s, 2H),3.41-3.40 (m, 5H), 2.50-2.39 (m, 4H), 1.28 (d, J=8.0 Hz, 3H). LCMS:(Method A) 361.0 (M+H), Rt. 2.01 min, 99.2% (Max). HPLC: (Method A) Rt.2.03 min, 98.5% (Max).

Example 492-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxamide

Step 1:Ethyl-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylate

The title compound was synthesized following general procedure D, usingethyl 2-(piperazin-1-yl)thiazole-4-carboxylate hydrochloride (Example17, Step 2, 5.0 g, 20.4 mmol) and Intermediate 3 (4.97 g, 24 mmol). Thecrude product was purified by flash chromatography. Yield: 54% (4.5 g,black oil).

Step 2:2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylicacid

To a stirred solution ofethyl-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylate(4.5 g, 11.1 mmol) in THF (20 mL), 10% NaOH (50 mL) was added slowly.

The reaction mixture was stirred at room temperature for overnight. Itwas concentrated under vacuum, neutralized with HCl (2 N in water) topH=6 and extracted with DCM (25 mL). The organic layer was washed withwater (10 mL), brine (25 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure afford the title compound (paleyellow solid). ¹H NMR (400 MHz, CDCl₃): δ 7.44 (s, 1H), 6.94-6.76 (m,3H), 4.26 (s, 4H), 3.65-3.49 (m, 5H), 2.59-3.54 (m, 4H), 2.49-2.45 (m,4H), 1.26 (d, J=4.8 Hz, 3H), LCMS: (Method A) 376.0 (M+H), Rt. 2.36 min,79.7% (Max).

Step 3:2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxamide

The title compound was synthesized according to the same procedure asdescribed for Example 30, using2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylicacid and NH₃ in THF. The crude product was purified by flashchromatography (off white solid). ¹H NMR (400 MHz, DMSO-d₆): ¹H NMR (400MHz, DMSO-d₆): δ 7.39 (br s, 2H), 7.35 (s, 1H), 6.80-6.76 (m, 3H), 4.21(s, 4H), 3.38-3.38 (m, 5H), 2.49-2.45 (m, 4H), 1.27-1.23 (m, 3H). LCMS:(Method A) 375.0 (M+H), Rt. 2.21 min, 96.1% (Max). HPLC: (Method A) Rt.2.28 min, 96.6% (Max).

Example 502-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide

The title compound was synthesized according to the same procedure asdescribed for Example 30, using2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylicacid and MeNH₂ in THF. The crude product was purified by flashchromatography (yellow oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.07 (q, J=4.0Hz, 1H), 7.33 (s, 1H), 6.76-6.39 (m, 3H), 4.21 (s, 4H), 3.38-3.32 (m,5H), 2.75-2.71 (m, 3H), 2.49-2.48 (m, 4H), 1.26-1.25 (m, 3H). LCMS:(Method A) 389.0 (M+H), Rt. 2.38 min, 95.9% (Max). HPLC: (Method A) Rt.2.46 min, 97.7% (Max).

Example 51 Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

Step 1: tert-Butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate

To a stirred solution of 1-boc-piperazine (6.0 g, 31.5 mmol) in DMF (50mL), triethyl amine (7 mL, 46.00 mmol) and 5-bromo-2-chloropyrimidine(6.3 g, 37.00 mmol) were added and the reaction mixture was stirred at90° C. for 8 h. The reaction mixture was concentrated under reducedpressure. Water (50 mL) was added and the desired product was extractedwith DCM (150 mL). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified byflash chromatography (10% EtOAc in pet ether) to afford the titlecompound. Yield: 76% (7 g, white). ¹H NMR (400 MHz, DMSO-d₆): δ 8.46 (s,2H), 3.68-3.67 (m, 4H), 3.39-3.37 (m, 4H), 1.40 (s, 9H). LCMS: (MethodA) 289.0 (M+H), Rt. 5.19 min, 99.05% (Max).

Step 2: 2-(4-(t-Butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylicacid

To a stirred solution of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5 g, 14.5 mmol) indry THF (50 mL), n-BuLi (13.5 mL, 21.7 mmol, 1.6 M in THF) was addeddropwise at −75° C. and stirred for 2 h at the same temperature. Dry CO₂gas was passed through the reaction mixture for 1 h. The reaction wasstirred for 30 min at same temperature and 30 min at rt. It was cooledto 0° C. and quenched by using 10% ammonium chloride solution. Theproduct was extracted with DCM (150 mL). The organic layer was washedwith water (50 mL), brine (50 mL) and dried over anhydrous Na₂SO₄. Afterevaporation of the solvents, the title compound was isolated and used inthe next step without further purification. Yield: 55% (2.5 g, paleyellow oil). LCMS: (Method A) 308.0 (M+H), Rt. 3.61 min, 55.64% (Max).

Step 3: Ethyl 2-(piperazin-1-yl)pyrimidine-5-carboxylate

To a stirring solution of2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid(2.0 g, 6.0 mmol) in EtOH (250 mL), SOCl₂ (1.7 mL, 16.23 mmol) was addedslowly at 0° C. and the mixture was stirred at 90° C. for 15 h. It wasconcentrated under reduced pressure to afford the title compound (offwhite solid). LCMS: (Method A) 236 (M+H), Rt. 2.14, 49.8% (Max).

Step 4: Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a stirring solution of ethyl2-(piperazin-1-yl)pyrimidine-5-carboxylate (2.5 g, 9.0 mmol),diisopropyl ethyl amine (5.9 mL, 27.0 mmol) in dry acetonitrile (50 mL),Intermediate 1 (2.08 g, 11.0 mmol) was added at rt and the reactionmixture was stirred at 80° C. overnight. The reaction mixture wasconcentrated under vacuum and the resulting crude product was purifiedby flash chromatography (50% EtOAC in pet ether) to afford the titlecompound (yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s, 2H), 6.90(s, 1H), 6.85-6.83 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.05 (d,J=2.8 Hz, 1H), 5.91 (d, J=2.8 Hz, 1H), 4.28-4.23 (q, J=7.2 Hz, 2H),3.82-3.81 (m, 4H), 3.49 (q, J=6.8 Hz, 1H), 2.55-2.44 (m, 2H), 2.43-2.33(m, 2H), 1.29-1.24 (m, 6H). LCMS: (Method A) 385 (M+H), Rt. 3.23 min,94.1% (Max). HPLC: (Method A) Rt. 3.23 min, 99.14% (Max).

Example 52(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)methanol

The title compound was synthesized following general procedure A fromExample 51. The crude product was purified by flash chromatography (30%EtOAc in pet ether) to afford the title compound (off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 8.27 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=8 Hz,1H), 6.75 (d, J=8.0 Hz, 1H), 5.99 (m, 2H), 5.05 (t, J=5.2 Hz, 1H), 4.30(d, J=5.2 Hz, 2H), 3.67 (s, 4H), 3.36-3.34 (m, 1H), 2.43-3.32 (m, 4H),1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 343.0 (M+H), Rt. 2.16 min,95.05% (Max). HPLC: (Method A) Rt. 2.11 min, 97.35% (Max).

Example 532-(4-(1-(2,3-dihydrobenzofuran-5-yl)ethyl)piperazin-1-yl)pyrimidine

To a solution of 2-(piperazin-1-yl)pyrimidine (0.8 g, 4.8 mmol),diisopropylethylamine (3.0 mL, 5.7 mmol) in ACN (20 mL), Intermediate 5(1.04 g, 5.7 mmol) was added at rt and the resulting mixture was stirredovernight. It was diluted with water (5 mL) and extracted with DCM (2×50mL). The combined organic layer was dried over Na₂SO₄ and concentratedunder vacuum. The crude product was purified by MD Autoprep (Method B)to afford the title compound (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ8.31 (d, J=4.8 Hz, 2H), 7.16 (s, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.67 (d,J=8.0 Hz, 1H), 6.58 (t, J=4.8 Hz, 1H), 4.48 (t, J=8.8 Hz, 2H), 3.67 (m,4H), 3.34 (t, J=6.8 Hz, 1H), 3.14 (m, 2H), 2.42-2.38 (m, 2H), 2.35-2.31(m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 311.2 (M+H), Rt. 2.511min, 98.68% (Max). HPLC: (Method A) Rt. 2.52 min, 99.82% (Max).

Example 54N-(4-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-2-yl)acetamide

To a stirred solution of Example 46 (0.35 g, 1.0 mmol) in dry DCM (3.5mL), pyridine (0.2 mL, 2.1 mmol), acetic anhydride (0.12 mL, 1.3 mmol)and DMAP (0.006 g, 0.5 mmol) were added at rt. The resulting mixture wasstirred for 5 h at rt and overnight at 50° C. It was diluted with ethylacetate (100 mL) and washed with HCl (1.5N), water, brine, dried overNa₂SO₄ and concentrated under vacuum. The resulting crude product waspurified by MD Autoprep (Method C) to afford the title compound (offwhite solid). ¹H NMR (400 MHz, MeOH-d₄): δ 7.99 (s, 1H), 6.88 (s, 1H),6.77 (s, 2H), 6.54 (br. s, 1H), 5.93 (s, 2H), 3.71 (s, 4H), 3.40 (q,J=6.8 Hz, 1H), 2.61-2.57 (m, 2H), 2.51-2.47 (m, 2H), 2.24 (s, 3H), 1.38(d, J=6.8 Hz, 3H). LCMS: (Method A) 370.2 (M+H), Rt. 1.88 min, 95.01%(Max). HPLC: (Method A) Rt. 1.83 min, 98.7% (Max).

Example 551-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-nitropyridin-2-yl)piperazine

To a stirred solution of Intermediate 2 (0.2 g, 2.1 mmol), Et₃N (1.2 mL,8.5 mmol) in dry DMF (5 mL), 2-chloro-5-nitropyridine (0.44 g, 2.8 mmol)was added at rt. The resulting mixture was stirred at 120° C. for 20 h.The completion of the reaction was monitored by TLC. The reactionmixture was diluted with water (10 mL) and extracted with EtOAc (25 mL).The organic layer was dried over anhydrous Na₂SO₄ and concentrated undervacuum. The resulting crude product was purified by flash chromatographyto afford the title compound (yellow solid). ¹H NMR (400 MHz, DMSO-d₆):δ 8.93 (d, J=2.8 Hz, 1H), 8.19 (dd, J=9.6, 2.8 Hz, 1H), 6.91-6.89 (m,2H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (br s, 2H),3.73 (s, 4H), 3.40 (q, J=6.4 Hz, 1H), 2.41-2.38 (m, 4H), 1.29 (d, J=6.4Hz, 3H). LCMS: (Method A) 357.0 (M+H), Rt. 2.98 min, 96.03% (Max). HPLC:(Method A) Rt. 3.03 min, 95.35% (Max).

Example 56(R)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamideor(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide

The two enantiomers of Example 30 were separated by chiral preparativeHPLC (Method PG). The first eluting compound has a Rt. 15.74 min (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.99 (q, J=4.8 Hz, 1H), 7.34 (s,1H), 6.90 (d, J=1.2 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0,1.2 Hz, 1H), 5.99 (s, 2H), 3.50-3.42 (m, 5H), 2.72 (d, J=4.8 Hz, 3H),2.50-2.49 (m, 4H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 375 (M+H),Rt. 2.35 min, 98.15% (Max). HPLC: (Method A) Rt. 2.38 min, 97.08% (Max),96.58% (254 nm). Chiral HPLC: (Method E) Rt. 15.74 min, 100.00%. Example56 corresponds to the second eluting compound, with Rt. 28.85 min (whitesolid). ¹HNMR (400 MHz, DMSO-d₆): δ 7.99 (q, J=4.8 Hz, 1H), 7.34 (s,1H), 6.90 (d, J=1.2 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.76 (dd, J=8.0,1.2 Hz, 1H), 5.99 (s, 2H), 3.50-3.41 (m, 5H), 2.72 (d, J=4.8 Hz, 3H),2.50-2.43 (m, 4H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 375.0 (M+H),Rt. 2.34 min, 99.94% (Max). HPLC: (Method A) Rt. 2.37 min, 99.77% (Max).Chiral HPLC: (Method E) Rt. 28.85 min, 100.00%

Example 57(R)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamideor(S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide

The two enantiomers of Example 50 were separated by chiral preparativeHPLC (Method PG). The first eluting compound has a Rt. 16.29 min (yellowsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.98 (q, J=4.4 Hz, 1H), 7.34 (s,1H), 6.81-6.74 (m, 3H), 4.22 (s, 4H), 3.42-3.39 (m, 5H), 2.73 (d, J=4.8Hz, 3H), 2.48-2.41 (m, 4H), 1.27 (t, J=6.4 Hz, 3H). LCMS: (Method A).389.0 (M+H), Rt. 2.40 min, 99.14% (Max). HPLC: (Method A) Rt. 2.36 min,99.63% (Max). Chiral HPLC: (Method E) Rt, 16.29 min, 100% (max). Example57 corresponds to the second eluting compound, with Rt. 33.49 min(yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.98 (d, J=4.4 Hz, 1H),7.34 (s, 1H), 6.81-6.74 (m, 3H), 4.21 (s, 4H), 3.42-3.37 (m, 5H), 2.73(d, J=4.8 Hz, 3H), 2.46-2.41 (m, 4H), 1.26 (t, J=6.4 Hz, 3H). LCMS:(Method A). 389.0 (M+H), Rt. 2.34 min, 98.58% (Max). HPLC: (Method A)Rt. 2.37 min, 99.28% (Max). Chiral HPLC: (Method E) Rt. 33.49 min,99.66% (max).

Example 586-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyridin-3-amine

To a stirred solution of Example 55 (0.20 g, 5.6 mmol) in methanol (4.0mL), Pd/C (0.02 g, 10% w/w) was added at rt and the mixture was stirredovernight under hydrogen atmosphere (5 Kg/cm²) at rt. The reactionmixture was filtered through celite and washed with methanol (10 mL).The organic layer was dried over anhydrous Na₂SO₄ and concentrated undervacuum. The resulted crude product was purified by MD Autoprep (MethodC) to afford the title compound (dark oil). ¹H NMR (400 MHz, DMSO-d₆): δ7.57 (d, J=2.8 Hz, 1H), 6.90-6.88 (m, 2H), 6.84 (d, J=8.0 Hz, 1H), 6.76(d, J=8.0 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 5.98 (m, 2H), 4.55 (s, 2H),3.33 (br m, 1H), 3.18 (s, 4H), 2.38-2.36 (m, 4H), 1.27 (d, J=6.4 Hz,3H). LCMS: (Method A) 327.2 (M+H), Rt. 1.85 min, 98.76% (Max). HPLC:(Method A) Rt. 1.81 min, 99.66% (Max).

Example 59 and Example 60(R)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamideand(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide

Step 1: Lithium2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

To a stirred solution of Example 27 (1.8 g, 3.86 mmol) in THF (14 mL)MeOH (4 mL) and H₂O (2 mL) was added LiOH.H₂O (395 mg, 9.65 mmol). Thereaction mixture was stirred at 50° C. for 3 h. The completion of thereaction was monitored by TLC. The reaction mixture was concentratedunder vacuum. The resulting crude product was suspended in toluene andthe solvents were evaporated again. It was used in the next step withoutany further purification. Yield: 89% (1.5 g, off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.73 (s, 1H), 6.88-6.82 (m, 2H), 6.75-6.73 (m,1H), 5.97 (s, 2H), 3.67-3.32 (m, 5H), 2.87-2.59 (m, 4H), 1.32-1.15 (m,3H). LCMS: (Method A) 362.0 (M+H), Rt. 2.26 min, 88.6% (Max).

Step 2:(R)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamideand(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide

To a stirred solution of lithium2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate(500 mg, 1.33 mmol) in DMF (10 mL), DIPEA (0.7 mL, 3.99 mmol), ethylamine (2 M in THF, 1 mL, 2.00 mmol) and HATU (607 mg, 1.60 mmol) wereadded at 0° C. The reaction mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under vacuum anddiluted with DCM. It was washed with water, brine and dried overanhydrous Na₂SO₄. The crude product was purified by flashchromatography. Both enantiomers were separated by chiral preparativeHPLC (Method PF). Example 59 corresponds to the first eluting compoundwith a Rt. 17.99 min (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.19(t, J=5.6 Hz, 1H), 7.74 (s, 1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz, 1H),6.76 (d, J=6.4 Hz, 1H), 5.99 (s, 2H), 3.21-3.17 (m, 2H), 2.48-2.39 (m,4H), 1.28 (d, J=6.4 Hz, 3H), 1.07 (t, J=7.2 Hz, 3H). LCMS: (Method A)389.2 (M+H), Rt. 2.47 min, 97.4% (Max). HPLC: (Method A) Rg. 2.43 min,99.9% (Max). Chiral HPLC: (Method D) Rt. 17.99 min, 100.00%. Example 60corresponds to the second eluting compound with a Rt. 19.92 min (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.19 (t, J=5.6 Hz, 1H), 7.74 (s,1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=6.8 Hz, 1H), 5.99(s, 2H), 3.21-3.17 (m, 2H), 2.48-2.33 (m, 4H), 1.28 (d, J=6.8 Hz, 3H),1.07 (t, J=7.2 Hz, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 2.46 min,99.3% (Max). HPLC: (Method A) Rt. 2.43 min, 99.9% (Max). Chiral HPLC:(Method D) Rt. 19.92 min, 100.00%.

Example 61(R)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamideor(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamide

The two enantiomers of Example 47 were separated by chiral preparativeHPLC (Method PF). The first eluting compound has a Rt. 14.07 min (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.58 (s, 1H), 6.90 (s, 1H), 6.85(s, 1H), 6.76 (s, 1H), 5.99 (s, 2H), 3.44-3.42 (m, 5H), 3.07 (br m, 6H),2.47-2.39 (m, 4H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 389.0 (M+H),Rt. 2.39 min, 99.5% (Max). HPLC: (Method A) Rt. 2.37 min, 99.6% (Max).Chiral HPLC: (Method D) Rt. 14.07 min, 100.00%. Example 61 correspondsto the second eluting compound with Rt. 16.06 min (white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.58 (s, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 6.76 (s,1H), 5.99 (s, 2H), 3.44-3.42 (m, 5H), 3.07 (br m, 6H), 2.50-2.39 (m,4H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 2.44 min,95.3% (Max). HPLC: (Method A) Rt. 2.37 min, 99.9% (Max). Chiral HPLC:(Method D) Rt. 16.06 min, 99.7%.

Example 62(S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamideor(R)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide

Step 1: Ethyl2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

To a stirred solution of Intermediate 4 (3.4 g, 11.94 mmol) in dry DMF(50 mL), ethyl 2-bromothiazole-5-carboxylate (Example 27, Step 1, 2.8 g,11.94 mmol) and TEA (5.0 mL, 35.82 mmol) were added at 0° C. Theresulting mixture was stirred at 120° C. overnight. It was cooled to rt,diluted with EtOAc, washed with water, brine, dried over anhydrousNa₂SO₄ and concentrated under vacuum. The resulting crude product waspurified by flash chromatography to afford the title compound. Yield:64% (3.1 g, pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (s,1H), 6.79-6.74 (m, 3H), 4.19-4.14 (m, 7H), 3.48-3.32 (m, 4H), 2.42-2.36(m, 4H), 1.26-1.19 (m, 6H). LCMS: (Method A) 404.0 (M+H), Rt. 3.19 min,96.5% (Max).

Step 2: Lithium2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

The title compound was synthesized according to the protocol describedfor Example 60, Step 1, using ethyl2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylateas starting material. The resulting product was used in the next stepwithout further purification. Yield: 86% (2.5 g, off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 7.16 (s, 1H), 6.79-6.72 (m, 3H), 4.20 (s, 4H),3.34-3.29 (m, 5H), 2.44-2.28 (m, 4H), 1.24 (d, J=8.8 Hz, 3H). LCMS:(Method A) 376.0 (M+H), Rt. 2.34 min, 97.4% (Max).

Step 3:(S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamideor(R)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide

The title compound was synthesized according to the protocol describedfor Example 60, Step 2, using lithium2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylateas starting material. The crude mixture was purified by flashchromatography followed by chiral preparative HPLC (Method PE) toseparate both enantiomers. The first fraction was concentrated to giveExample 62 (Rt. 19.00 min) (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ8.19 (t, J=5.2 Hz, 1H), 7.74 (s, 1H), 6.81-6.74 (m, 3H), 4.22 (s, 4H),3.42-3.35 (m, 5H), 3.22-3.16 (m, 2H), 2.50-2.33 (m, 4H), 1.27 (d, J=6.8Hz, 3H), 1.07 (t, J=7.2 Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.50min, 98.4% (Max). HPLC: (Method A) Rt. 2.47 min, 98.2% (Max). ChiralHPLC: (Method A) Rt. 19.00 min, 100%. The second enantiomer had a Rt.29.37 min (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.19 (t, J=5.6 Hz,1H), 7.74 (s, 1H), 6.81-6.74 (m, 3H), 4.22 (s, 4H), 3.42-3.37 (m, 5H),3.22-3.17 (m, 2H), 2.50-2.41 (m, 4H), 1.27 (d, J=6.4 Hz, 3H), 1.07 (t,J=7.2 Hz, 3H). LCMS: (Method A) 403.2 (M+H), Rt. 2.51 min, 99.6% (Max).HPLC: (Method A) Rt. 2.47 min, 98.9% (Max). Chiral HPLC: (Method A) Rt.29.37 min, 100%.

Example 63 and Example 64(R)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamideand(S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamide

The title compounds were synthesized according to the protocol describedfor Example 59 and Example 60, Step 2, using lithium2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate(Example 62, Step 2) and dimethyl amine as starting material. The crudemixture was purified by flash chromatography. Both enantiomers wereseparated by chiral preparative HPLC (Method PF). The first fractioncorresponds to Example 63 (Rt. 17.78 min) (white solid). ¹H NMR (400MHz, DMSO-d₆): δ 7.58 (s, 1H), 6.81-6.75 (m, 3H), 4.22 (s, 4H),3.44-3.38 (m, 5H), 3.06 (br. s, 6H), 2.47-2.39 (m, 4H), 1.27 (d, J=6.8Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.42 min, 99.3% (Max). HPLC:(Method A) Rt. 2.41 min, 99.6% (Max). Chiral HPLC: (Method D) Rt. 17.78min, 100.00%. The second fraction corresponds to Example 64 (Rt. 21.09min) (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.58 (s, 1H), 6.81-6.77(m, 3H), 4.22 (s, 4H), 3.44-3.38 (m, 5H), 3.12-2.99 (m, 6H), 2.46-2.39(m, 4H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.43min, 99.8% (Max). HPLC: (Method A) Rt. 2.40 min, 99.8% (Max). ChiralHPLC: (Method D) Rt. 21.09 min, 97.38%.

Example 65 and Example 66(R)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-5-carboxamideand(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-5-carboxamide

The title compounds were synthesized according to the proceduredescribed for Example 59 and Example 60 using methyl amine (2M in THF)as reagent. The crude mixture was purified by flash chromatographyfollowed by chiral preparative HPLC (Method PF) to separate enantiomers.The first fraction was concentrated to give Example 65 (white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 8.16 (d, J=4.4 Hz, 1H), 7.72 (s, 1H), 6.89 (s,1H), 6.85 (d, J=7.6 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (br s, 2H),3.43-3.42 (m, 5H), 2.69 (d, J=4.4 Hz, 3H), 2.47-2.33 (m, 4H), 1.28 (d,J=6.4 Hz, 3H). LCMS: (Method A) 375.0 (M+H), Rt. 2.23 min, 99.0% (Max).HPLC: (Method A) Rt. 2.19 min, 99.6% (Max). Chiral HPLC: (Method D) Rt.15.48 min, 98.91%.

The second fraction was concentrated to give Example 66 (white solid).¹H NMR (400 MHz, DMSO-d₆): δ 8.16 (q, J=4.8 Hz, 1H), 7.72 (s, 1H), 6.90(s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (br s,2H), 3.43-3.41 (m, 5H), 2.69 (d, J=4.8 Hz, 3H), 2.48-2.39 (m, 4H), 1.28(d, J=6.8 Hz, 3H). LCMS: (Method A) 375.0 (M+H), Rt. 2.23 min, 97.4%(Max). HPLC: (Method A) Rt. 2.19 min, 96.9% (Max). Chiral HPLC: (MethodD) Rt. 18.44 min, 100.00%

Example 67(2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(morpholino)methanone

The title compound was synthesized according to the procedure describedfor Example 59 and Example 60 using morpholine as reagent. Bothenantiomers were not separated in this example (pale brown solid). ¹HNMR (400 MHz, DMSO-d₆): δ 7.55 (s, 1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz,1H), 6.76 (d, J=7.6 Hz, 1H), 5.99 (s, 2H), 3.61 (br m, 8H), 3.45-3.42(m, 5H), 2.47-2.40 (m, 4H), 1.29 (d, J=6.4 Hz, 3H). LCMS: (Method A)431.0 (M+H), Rt. 2.41 min, 98.6% (Max). HPLC: (Method A) Rt. 2.38 min,97.1% (Max).

Example 68 and Example 69(R)-N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamideand(S)-N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of Example 41 (0.6 g, 1.8 mmol) in dry DCM (10mL), acetic anhydride (0.22 mL, 2.3 mmol) and DIPEA (0.615 mL, 3.6 mmol)were added at 0° C. and the reaction mixture was stirred at roomtemperature for 4 h. It was concentrated under vacuum and the crudeproduct was purified by recrystallization followed by enantiomerseparation by SFC. The first fraction was collected as Example 68 (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 11.66 (br s, 1H), 6.89 (s,1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (m, 2H),3.42-3.34 (m, 5H), 2.51-2.50 (m, 2H), 2.43-2.33 (m, 2H), 2.09 (s, 3H),1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 376.0 (M+H), Rt. 2.27 min,97.4% (Max). HPLC: (Method A) Rt. 2.29 min, 98.2% (Max). HPLC chiralpurity: (Method D) Rt. 24.02 min, 99.3% (Max). The second fraction wascollected as Example 69 (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ11.66 (br s, 1H), 6.89 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0,1.2 Hz, 1H), 5.99 (m, 2H), 3.41-3.34 (m, 5H), 2.55-2.47 (m, 2H),2.43-2.39 (m, 2H), 2.09 (s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (MethodA) 376.0 (M+H), Rt. 2.28 min, 95.8% (Max). HPLC: (Method A) Rt. 2.29min, 97.1% (Max). HPLC chiral purity: (Method D) Rt. 26.57 min, 97.5%(Max).

Example 702-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-amine

Step 1:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-nitropyrimidine

To a stirred solution of Intermediate 2 (1 g, 4.2 mmol) in dry DMF (10mL), Et₃N (2.3 mL, 16.8 mmol) and 2-chloro-5-nitropyrimidine (0.74 g,4.6 mmol) were added at rt and the resulting mixture was stirred at 120°C. for 20 h. It was diluted with water and extracted with EtOAc. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated undervacuum. The resulting crude product was purified by flash chromatographyto give the title compound (yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ9.08 (s, 2H), 6.92 (s, 1H), 6.85-6.83 (m, 1H), 6.77 (s, 1H), 5.98 (m,2H), 3.89 (s, 4H), 3.50 (s, 1H), 2.45-2.44 (m, 4H), 1.30 (br s, 3H).LCMS: (Method A) 358.0 (M+H), Rt. 3.00 min, 94.23% (Max).

Step 2:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-amine

To a stirred solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-nitropyrimidine(0.70 g, 1.9 mmol) in methanol (14 mL), Pd/C (0.07 g, 10% w/w) was addedat rt and the resulting mixture was stirred under hydrogen atmosphere (5kg/cm²) overnight at rt. The reaction mixture was filtered throughcelite and washed with methanol. The filtrate was dried over anhydrousNa₂SO₄ and concentrated under vacuum. The crude product was purified byflash chromatography to afford the title compound (yellow solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.86 (s, 2H), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz,1H), 6.75 (d, J=7.6 Hz, 1H), 6.46 (s, 2H), 5.98 (m, 2H), 3.48-3.45 (m,4H), 2.43-2.42 (m, 2H), 2.34-2.31 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS:(Method A) 328.2 (M+H), Rt. 1.91 min, 96.83% (Max). HPLC: (Method A) Rt.1.88 min, 95.85% (Max).

Example 71(R)-2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-N-methylthiazole-5-carboxamideor(S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-N-methylthiazole-5-carboxamide

The title compound was synthesized according to the procedure describedfor Example 62, using N,N,N trimethyl ethylene diamine as reagent. Thecrude product was purified by flash chromatography, followed by chiralpreparative HPLC using (Method PF) to separate both enantiomers. Thefirst eluting compound had Rt. 14.56 min (pale brown oil). ¹H NMR (400MHz, DMSO-d₆): δ 7.57 (s, 1H), 6.80-6.73 (m, 3H), 4.21 (s, 4H), 3.52 (t,J=6.4 Hz, 2H), 3.50-3.38 (m, 5H), 3.16-3.11 (m, 3H), 2.56-2.50 (m, 1H),2.49-2.38 (m, 5H), 2.32-2.10 (m, 6H), 1.26 (d, J=6.8 Hz, 3H). LCMS:(Method A) 460.2 (M+H), Rt. 2.12 min, 95.2% (Max). HPLC: (Method A) Rt.2.02 min, 96.9% (Max). Chiral HPLC: (Method D) Rt. 14.56 min, 97.43%.The second eluting compound corresponds to Example 71 (Rt. 16.81 min)(pale brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ 7.56 (s, 1H), 6.80-6.73(m, 3H), 4.21 (s, 4H), 3.50 (t, J=6.8 Hz, 2H), 3.48-3.36 (m, 5H), 3.09(br. s, 3H), 2.55-2.50 (m, 1H), 2.49-2.38 (m, 5H), 2.13 (s, 6H), 1.26(d, J=6.8 Hz, 3H). LCMS: (Method A) 460.2 (M+H), Rt. 2.13 min, 95.4%(Max). HPLC: (Method A) Rt. 2.03 min, 97.5% (Max). Chiral HPLC: (MethodD) Rt. 16.81 min, 98.36%.

Example 72N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

To a stirred solution of Example 70 (180 mg, 0.54 mmol) in dry pyridine(1.35 mL), acetic anhydride (0.06 mL, 0.65 mmol) was added at roomtemperature and the resulting mixture was stirred at 50° C. overnight.It was diluted with ethyl acetate (100 mL) and washed with HCl (1.5 N),water, brine and dried over Na₂SO₄. After evaporation of the solvents,the crude product was purified by flash chromatography to afford thetitle compound (yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.82 (s,1H), 8.46 (d, J=0.4 Hz, 2H), 6.89 (s, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.76(d, J=7.6 Hz, 1H), 5.98 (m, 2H), 3.64-3.62 (m, 4H), 3.36-3.34 (m, 1H),2.45-2.32 (m, 4H), 2.00 (s, 3H), 1.25 (d, J=6.8 Hz, 3H). LCMS: (MethodA) 370.2 (M+H), Rt. 2.30 min, 94.42% (Max). HPLC: (Method A) Rt. 2.22min, 95.29% (Max).

Example 73(2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-hydroxypiperidin-1-yl)methanone

Step 1:1-(2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carbonyl)piperidin-4-one

The title compound was synthesized according to the same procedure asdescribed for Example 62 using piperidine-4-one, hydrochloride, monohydrate as starting material (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.61 (s, 1H), 6.81-6.77 (m, 3H), 4.22 (s, 4H), 3.89 (t,J=6.1 Hz, 4H), 3.71 (t, J=6.1 Hz, 1H), 3.60 (t, J=4.2 Hz, 4H), 2.34-2.33(m, 8H), 1.27 (d, J=6.7 Hz, 3H). LCMS: (Method A) 457.0 (M+H), Rt. 2.42min, 90.5% (Max).

Step 2:(2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-hydroxypiperidin-1-yl)methanone

To a stirred solution of1-(2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carbonyl)piperidin-4-one(480 mg, 1.0 mmol) in dry MeOH (100 mL), NaBH₄ (59 mg, 1.5 mmol) wasadded slowly at 0° C. The reaction mixture was stirred at roomtemperature for 2 h. It was then concentrated under vacuum and theresulting crude product was dissolved in DCM, washed with water, brineand dried over anhydrous Na₂SO₄. The solvent was removed under reducedpressure to get the title compound. Yield: 69% (325 mg, off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.48 (s, 1H), 6.80-6.73 (m, 3H),4.78 (br. s, 1H), 4.21 (s, 4H), 3.92-3.88 (m, 2H), 3.72 (br s, 1H),3.42-3.35 (m, 4H), 3.33-3.25 (m, 2H), 2.46-2.38 (m, 4H), 1.75-1.74 (m,2H), 1.34-1.31 (m, 2H), 1.25 (d, J=6.8 Hz, 3H). LCMS: (Method A) 459.0(M+H), Rt. 2.32 min, 95.8% (Max). HPLC: (Method A) Rt. 2.33 min, 97.7%(Max).

Example 74 and Example 75(R)-(2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-methylpiperazin-1-yl)methanoneand(S)-(2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-methylpiperazin-1-yl)methanone

The title compounds were synthesized according to the same procedure asdescribed for Example 62, using N-methyl piperazine as startingmaterial. The crude mixture was purified by column chromatographyfollowed by chiral preparative HPLC using (Method PF) to separate bothenantiomers. The first eluting fraction was concentrated to give Example74 (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.52 (s, 1H),6.81-6.77 (m, 3H), 4.22 (s, 4H), 3.60 (br. s, 4H), 3.43-3.38 (m, 5H),2.45-2.33 (m, 8H), 2.19 (s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (MethodA) 458.2 (M+H), Rt. 2.02 min, 99.2% (Max). HPLC: (Method A) Rt. 2.01min, 99.7% (Max). Chiral HPLC: (Method D) Rt. 14.95 min, 98.36%. Thesecond eluting fraction was concentrated to give Example 75 (pale brownoil). ¹H NMR (400 MHz, DMSO-d₆): δ 7.52 (s, 1H), 6.81-6.74 (m, 3H), 4.22(s, 4H), 3.60-3.59 (m, 4H), 3.43-3.37 (m, 5H), 2.50-2.31 (m, 8H), 2.19(s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 458.2 (M+H), Rt. 2.02min, 98.3% (Max). HPLC: (Method A) Rt. 2.01 min, 99.2% (Max). ChiralHPLC: (Method D) Rt. 17.10 min, 97.39%.

Example 76N-(5-(4-(1-(3,4-difluorophenyl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

Step 1: 1-(3,4-Difluorophenyl)ethan-1-ol

To a stirred solution of 1-(3,4-difluorophenyl)ethan-1-one (2.0 g, 12.81mmol, Combi Blocks) in dry MeOH (40.0 mL), sodium borohydride (0.58 g,15.32 mmol, Loba chemie) was added portion wise at 0° C. The reactionmixture was stirred at rt for 4 h. The reaction mixture wasconcentrated. The residue was dissolved in DCM, washed with water, brinesolution, dried over anhydrous sodium sulfate and concentrated to affordthe title compound. Yield: 98% (2.0 g, colorless liquid). ¹H NMR (400MHz, DMSO-d₆): δ 7.38-7.29 (m, 2H), 7.17-7.13 (m, 1H), 5.31 (d, J=5.9Hz, 3H), 4.68 (q, J=8.3 Hz, 1H), 1.27 (d, J=8.3 Hz, 3H).

Step 2: 4-(1-chloroethyl)-1,2-difluorobenzene

To a stirred solution of 1-(3,4-difluorophenyl)ethan-1-ol (2.0 g, 12.64mmol) in dry DCM (100.0 mL), thionyl chloride (1.9 mL, 34.81 mmol,Spectrochem) was added slowly at 0° C. The reaction mixture was stirredat rt for 1 h. The completion of the reaction was monitored by TLC. Thereaction mixture was concentrated and resulting crude product was takenas such for next step. Yield: 90% (2.0 g, colorless liquid). ¹H NMR (400MHz, DMSO-d₆): δ 7.64-7.58 (m, 1H), 7.48-7.41 (m, 1H), 7.37-7.34 (m,1H), 5.36 (q, J=6.6 Hz, 1H), 1.78 (d, J=6.6 Hz, 3H).

Step 3:N-(5-(4-(1-(3,4-difluorophenyl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The title compound was synthesized by using general procedure D, using4-(1-chloroethyl)-1,2-difluorobenzene and Intermediate 7 as startingmaterials. The crude product was purified by flash chromatography (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (s, 1H), 7.42-7.35 (m,2H), 7.18-7.16 (m, 1H), 3.53 (q, J=6.4 Hz, 1H), 3.36-3.34 (m, 4H),2.51-2.40 (m, 4H), 2.09 (s, 3H), 1.30 (d, J=6.4 Hz, 3H). LCMS: (MethodA) 368.0 (M+H), Rt. 2.48 min, 97.02% (Max). HPLC: (Method A) Rt. 2.51min, 98.31% (Max).

Example 77 and Example 78:(R)-N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamideand(S)-N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

Example 72 was submitted to chiral preparative HPLC (Method PD). Thefirst eluting fraction was concentrated, affording Example 77 (paleyellow solid). ¹H NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 8.46 (s, 2H),6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.98 (m,2H), 3.63 (t, J=4.8 Hz, 4H), 3.31 (s, 1H), 2.44-2.33 (m, 4H), 2.00 (s,3H), 1.26 (d, J=6.0 Hz, 3H). LCMS: (Method A) 370.2 (M+H), Rt. 2.33 min,99.5% (Max). HPLC: (Method A) Rt. 2.24 min, 99.7% (Max). Chiral HPLC:(Method F) Rt. 31.24 min, 99.05%. The second eluting fraction wasconcentrated, affording Example 78 (pale yellow solid). 1H NMR (400 MHz,DMSO-d₆: δ 9.81 (s, 1H), 8.46 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz,1H), 6.76 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 3.63 (t, J=4.8 Hz, 4H), 3.31(s, 1H), 2.41-2.32 (m, 4H), 2.00 (s, 3H), 1.26 (d, J=6.0 Hz, 3H). LCMS:(Method A) 370.2 (M+H), Rt. 2.31 min, 99.5% (Max). HPLC: (Method A) Rt.2.25 min, 99.8% (Max). Chiral HPLC: (Method F) Rt. 21.26 min, 100.00%.

Example 794-((2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methyl)morpholine

Step 1:(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methanol

To a stirred solution of Example 27 (6.0 g, 16.4 mmol) in dry THF (70mL), Super hydride (65 mL, 65.0 mmol) was added slowly at 0° C. Thereaction mixture was stirred at rt for 2 h. The reaction mixture wasquenched with saturated NH₄Cl and extracted with ethyl acetate. Theorganic layer was separated, dried over anhydrous Na₂SO₄, concentratedunder vacuum. The crude product was purified by silica gel columnchromatography (10% MeOH in DCM) to afford the title compound (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.93 (s, 1H), 6.87-6.84 (d, J=12.8Hz, 1H), 6.81-6.75 (m, 1H), 6.74-6.72 (d, J=8.8 Hz, 1H), 5.96-5.96 (d,J=1.2 Hz, 2H), 5.18-5.16 (d, J=7.8 Hz, 1H), 3.41-3.28 (m, 3H), 2.52-2.37(m, 8H), 2.25 (s, 1H). LCMS: (Method A) 348.0 (M+H), Rt. 1.95 min,97.02% (Max).

Step 2:2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-(chloromethyl)thiazole

To a stirred solution of(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methanol(4.0 g, 11.5 mmol) in DCM (50 mL), SOCl₂ (1.6 mL, 23.0 mmol) was addedslowly at 0° C. and the resulting mixture was stirred at rt for 1 h. Itwas concentrated under vacuum. The resulting crude product was taken fornext step reaction without further purification. Yield: 96% (4.8 g,Yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 11.69 (s, 1H), 7.36-7.33 (m,1H), 7.13-6.98 (m, 2H), 6.07 (s, 2H), 4.46 (d, J=12.8 Hz, 2H), 4.04-3.69(m, 4H), 3.54-3.27 (m, 1H), 3.12-292 (m, 3H), 1.69 (d, J=6.0 Hz, 3H).LCMS: (Method A) 363 (M+H), Rt. 2.49 min, 86.01% (Max).

Step 3:4-((2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methyl)morpholine

To a stirred solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-(chloromethyl)thiazole(0.8 g, 2.0 mmol) in dry ACN (20 mL), DIPEA (1.8 mL, 8.0 mmol) andmorpholine (0.22 mL, 2.4 mmol) were added and the reaction mixture wasstirred at rt overnight. The reaction mixture was diluted with EtOAc andwashed with water. It was dried over anhydrous Na₂SO₄ and concentratedunder vacuum. The crude product was purified by flash chromatography(10% MeOH in DCM) to afford the title compound (pale yellow solid). ¹HNMR (400 MHz, DMSO-d₆): δ 6.95 (s, 1H), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz,1H), 6.75 (d, J=8.0 Hz, 1H), 5.99 (m, 2H), 3.54-3.53 (m, 4H), 3.48 (s,2H), 3.39 (q, J=6.8 Hz, 1H), 3.25-3.40 (m, 4H), 2.40-2.33 (m, 4H),1.28-1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 418.0 (M+H), Rt. 1.99 min,97.82% (Max). HPLC: (Method A) Rt. 1.78 min, 95.19% (Max).

Example 80N-((2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methyl)-N-methylacetamide

Step 1:1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)-N-methylmethanamine

To a stirred solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-(chloromethyl)thiazole(Example 79, Step 3, 1.2 g, 3.1 mmol) in dry ACN (20 mL), DIPEA (2.3 mL,12.4 mmol) and methyl amine (5.0 mL, 9.3 mmol, 2 M in THF) were addeddropwise. The resulting mixture was stirred at rt overnight. It wasdiluted with water and extracted with ethyl acetate. The organic layerwas separated, dried over anhydrous Na₂SO₄, concentrated under vacuum.The crude product was purified by flash chromatography (10% MeOH in DCM)to afford the title compound (yellow solid). LCMS: (Method A) 362.0(M+H), Rt. 1.96 min, 25.6% (Max).

Step 2:N-((2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methyl)-N-methylacetamide

To a stirred solution of1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)-N-methylmethanamine(0.1 g, 0.27 mmol), DIPEA (0.3 mL, 0.8 mmol) in dry DCM (10 mL), aceticanhydride (0.3 mL, 0.8 mmol) was added portion wise and the reactionmixture was stirred at rt for 12 h. It was quenched with water (10 mL)and extracted with ethyl acetate (25 mL). The organic layer was driedover anhydrous Na₂SO₄ and concentrated under vacuum. The resulting crudeproduct was purified by flash chromatography (10% MeOH in DCM) to affordthe title compound (pale yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ7.05 (d, J=9.6 Hz, 1H), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d,J=8.0 Hz, 1H), 5.99-5.98 (m, 2H), 4.40 (s, 2H), 3.39 (q, J=6.0 Hz, 1H),3.33-3.30 (m, 4H), 2.88 (s, 3H), 2.50-2.37 (m, 4H), 1.97 (s, 3H), 1.27(d, J=6.8 Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.19 min, 97.19%(Max). HPLC: (Method A) Rt. 2.14 min, 98.5% (Max).

Example 81(R)-(2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-hydroxypiperidin-1-yl)methanoneor(S)-(2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-hydroxypiperidin-1-yl)methanone

The two enantiomers of Example 73 were separated by chiral preparativeHPLC, (Method PH). The first eluting compound had Rt. 32.84 min (palebrown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.49 (s, 1H), 6.79-6.77 (m,3H), 4.78 (br. s, 1H), 4.22 (s, 4H), 3.93-3.90 (m, 2H), 3.73-3.72 (m,1H), 3.42-3.38 (m, 5H), 3.34-3.28 (m, 2H), 2.50-2.39 (m, 4H), 1.78-1.74(m, 2H), 1.38-1.26 (m, 5H). LCMS: (Method A) 459.0 (M+H), Rt. 2.32 min,95.9% (Max). HPLC: (Method A) Rt. 2.21 min, 94.4% (Max). Chiral HPLC:(Method B) Rt. 32.84 min, 100%. The second eluting compound was isolatedas Example 81 with Rt. 36.77 min (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.49 (s, 1H), 6.80-6.74 (m, 3H), 4.78 (br. s, 1H), 4.22 (s,4H), 3.94-3.88 (m, 2H), 3.74-3.72 (m, 1H), 3.43-3.38 (m, 5H), 3.33-3.26(m, 2H), 2.50-2.39 (m, 4H), 1.78-1.74 (m, 2H), 1.36-1.32 (m, 2H), 1.27(d, J=6.4 Hz, 3H). LCMS: (Method A) 459.0 (M+H), Rt. 2.32 min, 98.9%(Max). HPLC: (Method A) Rt. 2.23 min, 99.8% (Max). Chiral HPLC: (MethodB) Rt. 36.77 min, 94.52%.

Example 82N-(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of Intermediate 7 (0.4 g, 1.52 mmol) in dry ACN(10 mL), DIPEA (0.9 mL, 4.9 mmol) and Intermediate 6 (0.29 g, 1.52 mmol)were added at rt and the reaction mixture was stirred at 80° C. for 16h. It was cooled to rt and concentrated. The resulting mixture wasdissolved in ethyl acetate (70 mL), washed with water (10 mL), brine (10mL), dried over anhydrous sodium sulfate and concentrated. The crudeproduct was purified by flash chromatography to afford the titlecompound (orange solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H),8.94 (dd, J=1.6, 7.0 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (d, J=1.6 Hz,1H), 7.91 (dd, J=2.0, 8.6 Hz, 1H), 3.83-3.78 (m, 1H), 3.39-3.33 (m, 4H),2.67-2.60 (m, 2H), 2.56-2.50 (m, 2H), 2.09 (s, 3H), 1.44 (d, J=6.8 Hz,3H). LCMS: (Method A) 384.2 (M+H), Rt. 1.87 min, 98.4% (Max). HPLC:(Method A) Rt. 1.76 min, 99.0% (Max).

Example 83 6-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

To a stirred solution of 2-(piperazin-1-yl)pyrimidine hydrochloride(0.25 g, 1.52 mmol) in dry ACN (10 mL), DIPEA (0.9 mL, 4.9 mmol) andIntermediate 6 (0.29 g, 1.52 mmol) were added at rt and the reactionmixture was stirred at 80° C. for 16 h. It was cooled to rt andconcentrated. The crude mixture was dissolved in ethyl acetate (70 mL),washed with water (10 mL), brine (10 mL) and dried over anhydrous sodiumsulfate. After evaporation of the solvents, the crude product waspurified by flash chromatography to afford the title compound (orangesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.95-8.92 (m, 2H), 8.33 (d, J=4.8Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.92 (dd,J=1.6, 8.8 Hz, 1H), 6.60 (t, J=4.8 Hz, 1H), 3.77-3.71 (m, 5H), 2.60-2.55(m, 2H), 2.45-2.35 (m, 2H), 1.44 (d, J=6.8 Hz, 3H). LCMS: (Method A)321.0 (M+H), Rt. 2.01 min, 98.45% (Max). HPLC: (Method A) Rt. 1.92 min,99.1% (Max).

Example 84(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-4-yl)methanamine

Step 1:2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(chloromethyl)thiazole

To a stirred solution of Example 29 (1 g, 2.88 mmol) in dry DCM at 0°C., thionylchloride (0.4 mL, 8.64 mmol, spectrochem) was added dropwise.The reaction mixture was stirred at rt for 2 h. It was then concentratedand the resulting crude product was used without further purification.Yield: quantitative (1.2 g, pink solid). ¹H NMR (400 MHz, DMSO-d₆): δ7.73-7.35 (m, 1H), 7.31-6.95 (m, 2H), 6.05 (s, 2H), 5.74 (s, 1H),5.01-4.96 (m, 1H), 4.46 (s, 1H), 3.97-3.58 (m, 4H), 3.35-3.07 (m, 4H),1.21 ((d, J=8.8 Hz, 3H). LCMS: (Method A) 362.0 (M−H), Rt. 2.45 min,77.9% (Max).

Step 2:4-(azidomethyl)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole

To a stirred solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(chloromethyl)thiazole(1.2 g, 3.28 mmol) in dry DCM at 0° C., sodium azide (0.32 g, 4.9 mmol,spectrochem) was added in portion. The resulting mixture was heated at80° C. for 12 h. It was then concentrated. The residue was dissolved inDCM (50 mL), washed with water (15 mL) and dried over Na₂SO₄. Afterevaporation of the solvents, the crude product was used without furtherpurification. Yield: (1.1 g, colorless liquid). LCMS: (Method A) 373.0(M+H), Rt. 2.96 min, 78.9% (Max).

Step 3:(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-4-yl)methanamine

To a stirred solution of4-(azidomethyl)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole(1.1 g, 2.95 mmol) in THF (18 mL) and water (2 mL), triphenylphosphine(1.16 g, 4.4 mmol, spectrochem) was added in portion and the resultingmixture was heated at 60° C. for 12 h. The reaction mixture wasconcentrated in a vacuum. The residue was dissolved in DCM (25 mL),washed with water (10 mL) and dried over Na₂SO₄. After evaporation ofthe solvents, the crude product was purified by MD Autoprep (Method B)(off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.88 (t, J=2.4 Hz, 2H),6.86-6.83 (m, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 3.70 (s, 2H),3.40 (t, J=6.8 Hz, 1H), 3.33-3.28 (m, 4H), 2.42-2.37 (m, 4H), 1.90 (s,2H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 347.0 (M+H), Rt. 2.59 min,98.65% (Max). HPLC: (Method A) Rt. 1.86 min, 98.9% (Max).

Example 85N-((2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-4-yl)methyl)acetamide

To a solution of Example 84 (0.08 g, 0.23 mmol) in dry dichloromethane(5 mL), pyridine (0.01 mL, 0.11 mmol, spectrochem) and acetic anhydride(0.01 mL, 0.11 mmol, spectrochem) were added and the resulting mixturewas stirred at rt for 12 h. It was concentrated. The crude residue wasdissolved in DCM (15 mL), washed with water (5 mL) and dried overNa₂SO₄. After evaporation of the solvents, the crude product waspurified by MD Autoprep (Method C) (off white solid). ¹H NMR (400 MHz,CDCl3): δ 7.00 (s, 1H), 6.90 (s, 1H), 6.77 (s, 2H), 5.97 (s, 2H), 5.77(s, 1H), 4.43 (d, J=4.6 Hz, 2H), 3.48 (t, J=3.6 Hz, 5H), 2.56 (s, 4H),2.00 (s, 3H), 1.41 (s, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 2.02 min,94.37% (Max). HPLC: (Method A) Rt. 1.94 min, 92.8% (Max).

Example 86N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-2-yl)acetamide

Step 1:5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-2-amine

The title compound was synthesized following the general procedure D,using Intermediate 2 and 2-amino-5-bromo thiazole, hydrobromide salt asstarting materials. Yield: 66% (0.85 g, black solid). LCMS: (Method A)333.0 (M+H), Rt. 1.99 min, 57.8% (Max).

Step 2:N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-2-yl)acetamide

The title compound was synthesized via same procedure as described forExample 44, using5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-2-amineas starting material (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ11.68 (s, 1H), 6.89 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=7.6 Hz,1H), 6.57 (s, 1H), 5.99 (s, 2H), 3.38-3.33 (m, 1H), 3.02-2.92 (m, 4H),2.50-2.43 (m, 4H), 2.06 (s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (MethodA) 375.0 (M+H), Rt. 2.49 min, 97.9% (Max). HPLC: (Method A) Rt. 2.41min, 97.5% (Max).

Example 87N-(2-(4-(1-(3,4-Dichlorophenyl)ethyl)piperazin-1-yl)thiazol-5-yl)acetamide

The title compound was synthesized according to the general procedure D,using Intermediate 22 and Intermediate 2 as starting materials. Thecrude product was purified by column chromatography (yellow solid). ¹HNMR (400 MHz, DMSO-d₆): δ 11.68 (s, 1H), 7.61-7.57 (m, 2H), 7.33 (dd,J=8.4, 1.6 Hz, 1H), 6.58 (s, 1H), 3.53 (q, J=6.8 Hz, 1H), 2.99-2.96 (m,4H), 2.44-2.41 (m, 4H), 2.06 (s, 3H), 1.29 (d, J=6.8 Hz, 3H). LCMS:(Method A) 399.0 (M+H), Rt. 3.26 min, 97.0% (Max), 96.7% (220 nm). HPLC:(Method A) Rt. 3.16 min, 97.5% (Max).

Example 88N-(5-(4-(1-(4-chloro-3-methoxyphenyl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

Step 1: 4-chloro-N, 3-dimethoxy-N-methylbenzamide

To a stirred solution of 4-chloro-3-methoxy benzoic acid (2 g, 10.7mmol) in dry DCM (20 mL), triethylamine (4.4 mL, 32.1 mmol),N,O-dimethylhydroxylamine, hydrochloride (1.15 g, 11.7 mmol),propylphosphonic anhydride (T₃P) were added successively at 0° C. Theresulting mixture was stirred overnight at rt. It was diluted withethylacetate (50 mL), washed with water and dried over anhydrous Na₂SO₄.After evaporation of the solvents, the resulting crude product waspurified by flash chromatography (40% EtOAc in Hexane), affording thetitle compound. Yield: 73% (1.8 g, pale brown liquid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.49 (d, J=8.0 Hz, 1H), 7.30 (d, J=1.6 Hz, 1H), 7.18-7.15(m, 1H), 3.88 (s, 3H), 3.56 (s, 3H), 3.25 (s, 3H). LCMS: (Method A)230.0 (M+H), Rt. 3.43 min, 94.92% (Max).

Step 2: 1-(4-chloro-3-methoxyphenyl)ethan-1-one

To a stirred solution of 4-chloro-N,3-dimethoxy-N-methylbenzamide (2 g,8.70 mmol) in dry tetrahydrofuran (20 mL), methyl magnesium bromide (3 Min Et₂O, 5.8 mL, 17.4 mmol) was added dropwise at 0° C. and theresulting mixture was stirred at rt for 1 h. It was quenched withsaturated ammonium chloride solution (10 mL) and extracted with EtOAc(25 mL). The organic layer was washed with brine (15 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum. The crude product waspurified by flash column chromatography (45% EtOAc in hexane) to affordthe titled product (white solid). ¹H NMR (300 MHz, DMSO-d₆): δ 7.71-7.60(m, 1H), 7.52 (d, J=8.0 Hz, 3=1H), 7.11 (s, 3H), 3.88 (s, 3H), 2.50 (s,3H).

Step 3: 1-(4-chloro-3-methoxyphenyl)ethan-1-ol

The title compound was synthesized according to the general procedure Astarting with 1-(4-chloro-3-methoxyphenyl)ethan-1-one. The resultingcrude product was used without further purification. Yield: 98% (0.44 g,white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.45 (d, J=24.0 Hz, 1H),6.91-6.90 (m, 2H), 4.58-4.42 (m, 1H), 3.88 (s, 3H), 1.48 (d, J=8.0, 3H).

Step 4: 1-chloro-4-(1-chloroethyl)-2-methoxybenzene

The title compound was synthesized using the general procedure B,starting with 1-(4-chloro-3-methoxyphenyl)ethan-1-ol. The resultingcrude product was used without further purification. Yield: 88% (0.3 g,colorless liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.43 (d, J=8.2 Hz, 1H),7.25 (d, J=2.0 Hz, 1H), 7.10-7.07 (m, 1H), 5.38-5.36 (m, 1H), 3.88 (s,3H), 1.80 (d, J=6.8 Hz, 3H).

Step 5:N-(5-(4-(1-(4-chloro-3-methoxyphenyl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The title compound was synthesized by following general procedure D,using 1-chloro-4-(1-chloroethyl)-2-methoxybenzene and Intermediate 2 asstarting materials. The crude product was purified by flashchromatography (8% MeOH in DCM) to afford the title compound (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (s, 1H), 7.37 (d, J=8.4 Hz,1H), 7.09 (d, J=1.2 Hz, 1H), 6.92 (d, J=1.2, 8.4 Hz, 1H), 3.87 (s, 3H),3.49 (q, J=6.4 Hz, 1H), 3.35 (t, J=4.8 Hz, 4H), 2.46-2.42 (m, 4H), 2.10(s, 3H), 1.31 (d, J=6.8 Hz, 3H). LCMS: (Method A) 396.0 (M+H), Rt. 2.86min, 98.8% (Max). HPLC: (Method A) Rt. 2.83 min, 98.9% (Max).

Example 89(R)-N-(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamideor(S)-N-(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The two enantiomers of Example 82 were separated by chiral preparativeHPLC (Method PF). The first eluting compound has a retention time of15.34 min (Method D) (yellow solid). ¹H NMR (400 MHz, DMSO-d₆): 12.02(s, 1H), 8.93 (d, J=6.8 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H),7.91 (d, J=8.4 Hz, 1H), 3.80 (q, J=6.8 Hz, 1H), 3.39-3.37 (m, 4H),2.63-2.60 (m, 2H), 2.47-2.46 (m, 2H), 2.09 (s, 3H), 1.43 (d, J=6.8 Hz,3H). LCMS: (Method B) 384.2 (M+H), Rt. 1.88 min, 99.56% (Max). HPLC:(Method A) Rt. 1.77 min, 98.74% (Max). Chiral HPLC: (Method D) Rt. 15.34min, 99.77%. The second eluting compound corresponds to Example 89(yellow solid). ¹H NMR (400 MHz, DMSO-d₆): 11.94 (s, 1H), 8.93 (dd,J=1.6, 2.0 Hz, 2H), 8.09 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.91 (dd,J=1.6, 2.0 Hz, 1H), 3.80 (q, 1H, J=6.8 Hz), 3.39-3.37 (m, 4H), 2.63-2.60(m, 2H), 2.47 (m, 2H), 2.09 (s, 3H), 1.43 (d, J=6.8 Hz, 3H). LCMS:(Method B) 384.2 (M+H), Rt. 1.88 min, 99.62% (Max). HPLC: (Method A) Rt.1.77 min, 99.50% (Max). Chiral HPLC: (Method D) Rt. 17.11 min, 99.08%.

Example 90Ethyl-2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

To a stirred solution of Intermediate 6 (0.5 g, 2.6 mmol) in dry ACN (18mL), triethylamine (2.1 mL, 13.0 mmol, Spectrochem) and Intermediate 8(1.08 g, 3.8 mmol) were added and the resulting mixture was heated at90° C. for 12 h. It was concentrated, diluted with DCM (50 mL), washedwith water (20 mL) and dried over anhydrous Na₂SO₄. After evaporation ofthe solvents, the resulting crude product was purified by flashchromatography (4% methanol in DCM) to afford the title compound. Yield:58% (0.6 g, white solid). ¹H NMR (400 MHz, DMSO-d₆: δ 8.86 (s, 2H), 8.12(d, J=8.8 Hz, 1H), 8.03 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.87 (s, 1H),4.30 (q, J=7.2 Hz, 2H), 3.76 (d, J=5.6 Hz, 1H), 3.59-3.58 (m, 4H),2.71-2.70 (m, 2H), 2.60-2.59 (m, 2H), 1.51 (d, J=6.0 Hz, 3H), 1.34 (t,J=7.2 Hz, 3H). LCMS: (Method A) 398.2 (M+H), Rt. 2.61 min, 98.9% (Max).HPLC: (Method A) Rt. 2.64 min, 99.4% (Max).

Example 91 7-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoline

To a stirred solution of 2-(piperazin-1-yl)pyrimidine (0.17 g, 1.03mmol) in dry DMF (10 mL), DIPEA (0.6 mL, 3.13 mmol) and Intermediate 9(0.2 g, 1.03 mmol) were added at rt and the reaction mixture was stirredat 80° C. overnight. It was cooled to rt and concentrated. The resultingmixture was diluted in EtOAc (50 mL), washed with water (50 mL) anddried over anhydrous Na₂SO₄. After evaporating of the solvents, thecrude product was purified by flash chromatography to afford the titlecompound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.88 (t, J=2.8Hz, 1H), 8.87-8.31 (m, 3H), 7.91-7.96 (m, 2H), 7.626-7.64 (m, 1H),7.51-7.48 (m, 1H), 6.58 (t, J=4.8 Hz, 1H), 3.66-3.72 (m, 5H), 2.53-2.56(m, 2H), 2.37-2.43 (m, 2H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A)320.2 (M+H), Rt. 1.65 min, 99.0% (Max). HPLC: (Method A) Rt. 1.56 min,98.7% (Max).

Example 92N-methyl-2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxamide

Step 1:2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylic acid

To a stirred solution of Example 90 (0.5 g, 1.25 mmol) in dioxane (5mL), NaOH (10% in water, 2 mL) was added and the mixture was stirred atrt for 12 h. It was neutralized with 5 N HCl solution (25 mL) andextracted with DCM (20 mL). The organic phase was dried over anhydrousNa₂SO₄. After evaporating of the solvents, the crude product was usedwithout further purification. Yield: 50% (0.2 g, colourless oil). ¹H NMR(400 MHz, DMSO-d₆): δ 10.9 (s, 1H), 9.92 (s, 1H), 8.86 (s, 2H),3.22-3.17 (m, 4H), 3.02-2.78 (m, 4H), 2.06 (s, 3H). LCMS: (Method B)370.0 (M+H), Rt. 1.90 min, 67.5% (Max).

Step 2:N-methyl-2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxamide

To a stirred solution of2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylic acid(0.2 g, 0.5 mmol) in DCM (10 mL), DIPEA (0.5 mL, 2.0 mmol), methyl amine(2 M in THF, spectrochem, 0.03 mL, 1.00 mmol) and HATU (0.29 g, 0.7mmol, spectrochem) were added at 0° C. The reaction mixture was stirredat room temperature for 12 h. The completion of the reaction wasmonitored by TLC. The reaction mixture was concentrated under vacuum,diluted with DCM (25 mL), washed with water, brine and dried overanhydrous Na₂SO₄. After evaporation of the solvents, the crude productwas purified by flash chromatography to afford pure title product.Yield: 50% (100 mg, of fwhite solid). ¹H NMR (400 MHz, DMSO-d₆: δ8.94-8.93 (d, J=5.2 Hz, 2H), 8.15-8.14 (d, J=4.4 Hz, 1H), 8.10-8.08 (d,J=8.8 Hz, 1H), 8.00 (s, 1H), 7.92-7.90 (q, J=1.6 Hz, 1H), 7.71 (s, 1H),3.82-3.81 (d, J=6.8 Hz, 1H), 3.46-3.45 (d, J=4.8 Hz, 4H), 2.69-2.68 (d,J=4.4 Hz, 3H), 2.60 (t, J=6.4 Hz, 2H), 2.46 (s, 2H), 1.44-1.43 (d, J=6.8Hz, 3H). LCMS: (Method A) 383.2 (M+H), Rt. 1.86 min, 99.1% (Max). HPLC:(Method A) Rt. 1.73 min, 99.3% (Max).

Example 93N-(2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

To a stirred solution of Intermediate 10 (0.66 g, 2.6 mmol) in dry DMF(10 mL), triethylamine (1.4 mL, 10.4 mmol, Spectrochem) and Intermediate6 (0.5 g, 2.6 mmol) were added and the resulting mixture was heated at90° C. for 12 h. It was concentrated and the resulting residue wasdiluted with DCM (25 mL), washed with water (10 mL) and dried overNa₂SO₄. After evaporation of the solvents, the crude product waspurified by MD Autoprep (Method B) to afford the title compound (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆: δ 9.80 (s, 1H), 8.91 (dd, J=2,7.4 Hz, 2H), 8.45 (s, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.99 (d, J=1.6 Hz,1H), 7.92-7.90 (m, 1H), 3.82 (d, J=2 Hz, 1H), 3.65 (m, 4H), 2.55-2.51(m, 2H), 2.49-2.42 (m, 2H), 1.99 (s, 3H), 1.42 (d, J=6.8 Hz, 3H). LCMS:(Method A) 378.3 (M+H), Rt. 1.71 min, 99.83% (Max). HPLC: (Method A) Rt1.80 min, 99.66% (Max).

Example 946-(1-(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

To a stirred solution of2-(piperazin-1-yl)-4-(trifluoromethyl)pyrimidine hydrochloride (699 mg,2.6 mmol) in DMF (10 mL), TEA (1.4 mL, 10.38 mmol) and Intermediate 6(500 mg, 2.6 mmol) were added and the resulting mixture was stirred at90° C. overnight. It was concentrated under vacuum and the residue wasdissolved in DCM (15 mL), washed with water (10 mL) and dried overanhydrous Na₂SO₄. After evaporation of the solvents, the crude productwas purified by flash chromatography to afford the title compound (brownoil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.92 (dd, J=8.8, 1.6 Hz, 2H), 8.64(d, J=4.4 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.91(d, J=8.8, 1.6 Hz, 1H), 6.98 (d, J=4.4 Hz, 1H), 3.79-3.75 (m, 5H),2.59-2.54 (m, 2H), 2.48-2.41 (m, 2H), 1.43 (d, J=6.8 Hz, 3H). LCMS:(Method A) 389.30 (M+H), Rt. 3.09 min, 99.40% (Max). HPLC: (Method A) Rt3.07 min, 99.89% (Max).

Example 95 (S)-7-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)quinolone or(R)-7-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoline

To a stirred solution of 1-(2-pyrimidylpiperazine) (1.11 g, 6.8 mmol) indry DMF (20 mL), DIPEA (3.66 mL, 20.28 mmol) and Intermediate 9 (1.3 g,6.8 mmol) were added and the reaction mixture was stirred at 80° C.overnight. It was concentrated under vacuum and the crude residue wasdissolved in EtOAc (60 mL), washed with water (20 mL) and dried overanhydrous Na₂SO₄. After evaporation of the solvent, the crude productwas purified by flash chromatography followed by chiral preparative HPLC(Method PF) to separate both enantiomers. Example 95 corresponds to thesecond eluting fraction (pale yellow solid). ¹H NMR (400 MHz, DMSO-d₆):δ 8.89 (dd, J=4.4, 1.6 Hz, 1H), 8.35-8.31 (m, 3H), 7.95 (d, J=8.4 Hz,1H), 7.91 (s, 1H), 7.66 (dd, J=8.4, 1.6 Hz, 1H), 7.49 (dd, J=8.0, 4.0Hz, 1H), 6.59 (t, J=4.8 Hz, 1H), 3.72-3.68 (m, 5H), 2.56-2.51 (m, 2H),2.43-2.37 (m, 2H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 320.2 (M+H),Rt. 1.63 min, 99.56% (Max). HPLC: (Method A) Rt. 1.54 min, 99.3% (Max).Chiral HPLC: (Method D) Rt 12.96 min, 100%.

Example 96N-(2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

To a stirred solution of Intermediate 10 (320 mg, 1.24 mmol) in dry ACN(5 mL), DIPEA (3.66 mL, 20.28 mmol) and Intermediate 3 (270 mg, 1.36mmol) were added and the reaction mixture was stirred at 80° C.overnight. It was concentrated under vacuum and the crude product wasdissolved in EtOAc (30 mL), washed with water (10 mL) and dried overanhydrous Na₂SO₄. After evaporation of the solvents, the crude productwas purified by flash chromatography to afford the title compound (paleyellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.79 (s, 1H), 8.44 (s, 2H),6.76-6.74 (m, 3H), 4.19 (s, 4H), 3.61 (s, 4H), 2.38-2.31 (m, 4H), 1.98(s, 3H), 1.24 (d, J=6.4 Hz, 3H). LCMS: (Method A) 384.2 (M+H), Rt. 2.27min, 99.82% (Max). HPLC: (Method A) Rt. 2.26 min, 98.35% (Max).

Example 97N-(5-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The title compound was synthesized according the same procedure asExample 96, using Intermediate 7 and Intermediate 3 as startingmaterials. The crude product was purified by flash chromatographyfollowed by MD Autoprep (Method B) to give the title compound (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (s, 1H), 6.80-6.74 (m, 3H),4.21 (s, 4H), 3.37-3.33 (m, 5H), 2.43-2.39 (m, 4H), 2.09 (s, 3H), 1.26(d, J=6.8 Hz, 3H). LCMS: (Method A) 390.0 (M+H), Rt. 2.39 min, 98.62%(Max). HPLC: (Method A) Rt. 2.27 min, 97.05% (Max).

Example 982-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

Step 1: Ethyl 2-(methylthio)pyrimidine-5-carboxylate

To a stirred solution of ethyl-4-chloro-(2-methyl thio pyrimidine)5-carboxylate (10 g, 42.9 mmol) in THF/water (8:2, 100 mL), zinc powder(14.0 g, 0.21 mmol) followed by t-BuOH (2 mL) were added and theresulting mixture was heated at 90° C. of overnight. The reactioncompletion was monitored by LCMS. The mixture was filtered throughcelite and evaporated under vacuum. The crude product was dissolved indichloromethane (100 mL), washed with water (50 mL) and dried overNa₂SO₄. After evaporation of the solvents, the crude product waspurified by MD Autoprep (Method B) (colorless liquid). ¹H NMR (400 MHz,DMSO-d₆): 9.03 (s, 2H), 4.35 (q, J=7.1 Hz, 2H), 2.58 (s, 3H), 1.33 (t,J=7.08 Hz, 3H). LCMS: (Method A) 199.0 (M+H), Rt. 3.50 min, 99.7% (Max).

Step 2: Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate

To a stirred solution of ethyl 2-(methylthio)pyrimidine-5-carboxylate(2.8 g, 14.2 mmol) in tetrahydrofuran at 0° C., 3-chloroperbenzoic acid(7.8 g, 60.7 mmol, spectrochem) was added and the resulting solution wasstirred at rt for 3 h. It was concentrated. DCM was added and was washedwith water (25 mL) and 10% sodium bicarbonate solution (20 mL) and driedover Na₂SO₄. After evaporation of the solvents, the crude product waspurified by flash chromatography to afford the titled product. Yield:50.7% (1.65 g, off white solid). ¹H NMR (400 MHz, DMSO-d₆): 9.48 (s,2H), 4.43 (q, J=7.0 Hz, 2H), 3.48 (s, 3H), 1.37 (t, J=7.1 Hz, 3H), LCMS:(Method A) 230.9 (M+H), Rt. 2.33 min, 97.48% (Max).

Step 3: Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a stirred solution of Intermediate 2 (1.87 g, 6.94 mmol) in dryacetonitrile, potassium carbonate (2.87 g, 20.8 mmol, spectrochem) andethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate were added and theresulting mixture was at rt for 12 h. It was filtered through celite andconcentrated. Dichloromethane (25 mL) was added and the solution waswashed with water, brine and dried over Na₂SO₄. After evaporation of thesolvents, the crude product was purified by flash column chromatographyto afford the title compound (white solid). ¹H NMR (400 MHz, DMSO-d₆):8.74 (s, 2H), 6.85 (t, J=7.8 Hz, 2H), 6.75 (d, J=7.8 Hz, 1H), 5.98 (s,2H), 4.25 (q, J=6.8 Hz, 2H), 3.81 (s, 4H), 3.32 (s, 1H), 2.37-2.42 (m,4H), 1.28 (d, J=6.6 Hz, 6H). LCMS: (Method A) 385.2 (M+H), Rt. 3.22 min,98.88% (Max).

Step 4: Lithium2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a stirred solution of ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate(0.9 g, 2.34 mmol) in MeOH (2 mL), THF (7 mL) and water (1 mL) mixture,lithium hydroxide (0.24 g, 5.85 mmol, spectrochem) was added at 0° C.The resulting mixture was stirred at rt for 12 h. It was concentratedand the crude product was used without further purification. Yield: 90%(0.52 g, off white solid). LCMS: (Method A) 357.0 (M+H), Rt. 2.38 min,99.21% (Max).

Step 5:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

To a stirred solution of lithium2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate(300 mg, 0.82 mmol) in dry DMF (5 mL), methyl amine (0.09 mL, 0.988mmol, 2M in THF), DIPEA (0.45 mL, 2.47 mmol) and HATU (471 mg, 1.29mmol) were added and the resulting mixture was stirred at rt for 12 h.It was concentrated under vacuum and the crude product was diluted withDCM (20 mL), washed with water (15 mL) and dried over anhydrous Na₂SO₄.After evaporation of the solvents, the crude product was purified by MDAutoprep (Method B) to give the title compound (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.71 (s, 2H), 8.29 (q, J=4.4 Hz, 1H), 6.90 (d,J=1.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (dd, J=8.0, 1.2 Hz, 1H),5.98 (m, 2H), 3.78-3.76 (m, 4H), 3.39 (q, J=6.4 Hz, 1H), 2.74 (d, J=4.8Hz, 3H), 2.45-2.42 (m, 2H), 2.37-2.32 (m, 2H), 1.28 (d, J=6.4 Hz, 3H).LCMS: (Method A) 370.2 (M+H), Rt. 2.24 min, 97.69% (Max). HPLC: (MethodA) Rt. 2.19 min, 99.52% (Max).

Example 992-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylpyrimidine-5-carboxamide

The title compound was synthesized according the same protocol asExample 98, using dimethyl amine (2 M in THF) as reagent. The crudeproduct was purified by MD Autoprep (Method B) to afford the titlecompound (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.45 (s, 2H), 6.90(d, J=1.2 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (dd, J=8.0, 1.2 Hz, 1H),5.98 (m, 2H), 3.77-3.74 (m, 4H), 3.39 (q, J=6.4 Hz, 1H), 2.97 (s, 6H),2.47-2.42 (m, 2H), 2.38-2.33 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS:(Method A) 384.0 (M+H), Rt. 2.51 min, 99.94% (Max). HPLC: (Method A) Rt.2.35 min, 99.85% (Max).

Example 100N-(5-(4-(1-(4-chloroquinolin-7-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of Intermediate 7 (231 mg, 0.88 mmol) in dry ACN(10 mL), DIPEA (0.5 mL, 2.64 mmol) and Intermediate 12 (200 mg, 0.88mmol) were added at rt and the reaction mixture was stirred at 90° C.overnight. It was concentrated under vacuum and the resulting crudeproduct was diluted with DCM (25 mL), washed with water (10 mL), brine(10 mL) and dried over anhydrous Na₂SO₄. After evaporation of thesolvents, the crude product was purified by MD Autoprep (Method B) togive the title compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ12.00 (s, 1H), 8.83 (d, J=4.8 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.0 (brs, 1H), 7.81 (dd, J=8.8, 1.6 Hz, 1H), 7.74 (d, J=4.8 Hz, 1H), 3.77 (q,J=6.4 Hz, 1H), 3.38-3.35 (m, 4H), 2.67-2.59 (m, 4H), 2.08 (s, 3H), 1.42(d, J=6.4 Hz, 3H). LCMS: (Method A) 417.0 (M+H), Rt. 2.35 min, 96.55%(Max). HPLC: (Method A) Rt. 2.31 min, 96.43% (Max).

Example 101N-(2-(4-(1-(4-chloroquinolin-7-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

The title compound was synthesized according the same protocol asdescribed for the synthesis of Example 100, using Intermediate 10 andIntermediate 12 as starting materials. The crude product was purified byMD Autoprep (Method B) to give the title compound (off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 9.8 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.46 (s,2H), 8.19 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.73(d, J=4.8 Hz, 1H), 3.77 (q, J=6.4 Hz, 1H), 3.67-3.65 (m, 4H), 2.53-2.41(m, 4H), 1.99 (s, 3H), 1.41 (d, J=6.8 Hz, 3H). LCMS: (Method A) 411.0(M+H), Rt. 2.35 min, 97.54% (Max). HPLC: (Method A) Rt. 2.29 min, 98.92%(Max).

Example 1026-(1-(4-(5-Methylpyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

To a stirred solution of Intermediate 11 (600 mg, 2.16 mmol) in dry DMF(10 mL), TEA (1.2 mL, 8.66 mmol) and 2-chloro-5-methylpyrimidine (280mg, 2.16 mmol) were added at rt and the reaction mixture was stirred at90° C. overnight. It was concentrated under vacuum and the resultingcrude mixture was diluted with EtOAc (40 mL), washed with water (10 mL),brine (10 mL) and dried over anhydrous Na₂SO₄. After evaporation of thesolvents, the crude product was purified by flash chromatography to givethe title compound (brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.91 (d,J=7.2 Hz, 2H), 8.18 (s, 2H), 8.07 (s, J=8.8 Hz 1H), 7.99 (s, 1H), 7.90(d, J=8.8 Hz, 1H), 3.67-3.66 (m, 4H), 2.54-2.49 (m, 2H), 2.40-2.38 (m,2H), 2.05 (s, 3H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 335.2 (M+H),Rt. 2.14 min, 99.24% (Max). HPLC: (Method A) Rt. 2.21 min, 99.26% (Max).

Example 1036-(1-(4-(5-ethylpyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

The title compound was synthesized according the same protocol asdescribed for the synthesis of Example 102, using Intermediate 11 and2-chloro-5-ethylpyrimidine as starting materials. The crude product waspurified by flash chromatography to give the title compound (brown oil).¹HNMR (400 MHz, DMSO-d₆): δ 8.93 (d, J=6.0 Hz, 2H), 8.18 (s, 2H), 8.07(d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 3.75 (q, J=6.8Hz, 1H), 3.69-3.66 (m, 4H), 2.52-2.50 (m, 2H), 2.41-2.39 (m, 4H), 1.41(d, J=6.8 Hz, 3H), 1.11 (t, J=7.2 Hz, 3H). LCMS: (Method A) 349.2 (M+H),Rt. 2.47 min, 98.68% (Max). HPLC: (Method A) Rt. 2.47 min, 99.26% (Max).

Example 104(S)-6-(1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxalineor(R)-6-(1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

To a stirred solution of2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (500 mg,1.86 mmol) in dry DMF (10 mL), TEA (1.3 mL, 5.58 mmol) and Intermediate6 (394 mg, 2.05 mmol) were added at rt and the reaction mixture wasstirred at 90° C. overnight. The reaction mixture was concentrated undervacuum and the resulting residue was diluted with EtOAc (30 mL), washedwith water (10 mL), brine (10 mL) and dried over anhydrous Na₂SO₄. Afterevaporation of the solvents, the crude product was purified by flashchromatography followed by chiral preparative HPLC (Method PJ) toseparate both enantiomers. The second eluting fraction was concentratedto give the title compound (pale brown solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.90 (dd, J=6.8, 1.6 Hz, 2H), 8.65 (d, J=0.8, Hz, 2H), 8.07(d, J=8.4 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H),3.83-3.77 (m, 5H), 2.59-2.43 (m, 4H), 1.42 (d, J=6.8 Hz, 3H). LCMS:(Method A) 389.2 (M+H), Rt. 2.95 min, 99.43% (Max). HPLC: (Method A) Rt.2.99 min, 99.71% (Max). Chiral HPLC: (Method F) Rt 17.91 min, 99.63%.

Example 105N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)propionamide

To a stirred solution of Example 41 (310 mg, 1.2 mmol) in dry DCM (10mL), TEA (0.4 mL, 2.78 mmol) and propionyl chloride (94 mg, 1.02 mmol)were added at 0° C. and the resulting mixture was stirred at rtovernight. The reaction mixture was concentrated under vacuum and theresulting crude product was purified by flash chromatography to give thetitle compound (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 11.96 (s,1H), 6.83 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 5.98(m, 2H), 3.34-3.32 (m, 5H), 2.51-2.37 (m, 6H), 1.28 (d, J=6.8 Hz, 3H),1.04 (d, J=7.2 Hz, 3H). LCMS: (Method A) 390.0 (M+H), Rt. 2.57 min,99.27% (Max). HPLC: (Method A) Rt. 2.48 min, 99.7% (Max).

Example 106N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)butyramide

The title compound was synthesized according the same protocol asdescribed for the synthesis of Example 105, using butyryl chloride asacylating agent. The resulting crude product was purified by flashcolumn chromatography followed by MD Autoprep (Method B) to give thetitle compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 11.98 (s,1H), 6.89 (d, J=1.6 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0,1.6 Hz, 1H), 5.98 (m, 2H), 3.39 (q, J=5.6 Hz, 1H), 3.35-3.33 (m, 4H),2.56-2.40 (m, 4H), 2.36 (t, J=7.6 Hz, 2H), 1.61-1.55 (m, 2H), 1.28 (d,J=6.4 Hz, 3H), 0.86 (t, J=7.2 Hz, 3H). LCMS: (Method A) 404.2 (M+H), Rt.2.81 min, 97.58% (Max). HPLC: (Method A) Rt. 2.84 min, 99.12% (Max).

Example 107N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)isobutyramide

The title compound was synthesized according the same protocol asdescribed for the synthesis of Example 105, using isobutryl chloride asacylating agent. The crude product was purified by flash chromatographyto give the title compound (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ11.99 (s, 1H), 6.89 (d, J=1.2 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (dd,J=8.0, 1.2 Hz, 1H), 5.99 (m, 2H), 3.43 (q, J=6.8 Hz, 1H), 3.80-3.33 (m,4H), 2.72-2.65 (m, 1H), 2.44-2.32 (m, 4H), 1.28 (d, J=6.8 Hz, 3H), 1.09(d, J=6.8 Hz, 6H). LCMS: (Method A) 404.2 (M+H), Rt. 2.82 min, 98.33%(Max). HPLC: (Method A) Rt. 2.75 min, 99.73% (Max).

Example 108N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)cyclopropanecarboxamide

The title compound was synthesized according the same protocol asdescribed for the synthesis of Example 105, using cyclopropane carbonylchloride as acylating agent. The crude product was purified by flashchromatography followed by MD Autoprep (Method B) to give the titlecompound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.30 (s, 1H),6.89 (d, J=1.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0, 1.6 Hz,1H), 5.99 (m, 2H), 3.39 (q, J=6.4 Hz, 1H), 3.33-3.28 (m, 4H), 2.56-2.39(m, 4H), 1.88-1.87 (m, 1H), 1.28 (d, J=6.4 Hz, 3H), 0.90-0.83 (m, 4H).LCMS: (Method A) 402.2 (M+H), Rt. 2.63 min, 99.66% (Max). HPLC: (MethodA) Rt. 2.66 min, 99.76% (Max).

Example 1092-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-methylthiazole-5-carboxamide

To a stirred solution of lithium2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate(0.7 g, 18.37 mmol, Example 62, Step 2) in dry DMF (7 mL), methyl amine(2M in THF, 1.3 mL, 27.55 mmol), HATU (0.83 g, 22.0 mmol) and DIPEA (0.9mL, 55.1 mmol) were added and the reaction mixture was stirred overnightat rt. It was cooled to rt and concentrated. Water (15 mL) was added tothe resulting mixture and was extracted with EtOAc (2×30 mL). Theorganic layer was dried over anhydrous Na₂SO₄. After evaporation of thesolvents, the crude product was purified by MD Autoprep HPLC (Method B)to afford the title compound as off white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.14 (q, J=4.0, 1H), 7.70 (s, 1H), 6.77-6.74 (m, 3H), 4.40(s, 4H), 3.39-3.38 (m, 5H), 2.67 (d, J=4.4 Hz, 3H), 2.49-2.48 (m, 2H),2.44-2.38 (m, 2H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method A) 389.2 (M+H),Rt. 2.26 min, 97.94% (Max). HPLC: (Method A) Rt. 2.23 min, 98.53% (Max).

Example 110N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-chlorobenzamide

To a stirred solution of Example 41 (0.40 g, 1.2 mmol) in dry DCM (10mL), TEA (0.4 mL, 0.45 mmol) and 4-chlorobenzoyl chloride (0.28 g, 1.65mmol) were added at 0° C. and the resulting mixture was stirredovernight at rt. It was concentrated under vacuum and the resultingcrude product was purified by flash chromatography to give the titlecompound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): 12.69 (s, 1H),8.06 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 6.75-6.89 (m, 3H), 5.99(t, J=0.4 Hz, 2H), 3.39-3.42 (m, 5H), 2.42-2.45 (m, 4H), 1.28 (d, J=6.80Hz, 3H), LCMS: (Method A) 471.1 (M+H), Rt. 3.59 min, 98.8% (Max). HPLC:(Method A) Rt. 3.56 min, 98.7% (Max).

Example 1115-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-(4-chlorobenzyl)-1,3,4-thiadiazol-2-amine

To a stirred solution of Example 41 (0.3 g, 0.90 mmol) in dry1,2-dichloroethane (3 mL), titanium isopropoxide (0.8 mL, 2.71 mmol) and4-chlorobenzaldehyde (0.19 g, 1.35 mmol) were added and the reactionmixture was refluxed for 8 h. It was cooled to 0° C. and sodiumborohydride (0.17 g, 4.51 mmol) was added and the mixture was stirred atrt for 2 h. It was concentrated and water (15 mL) was added to theresulting crude product. It was extracted with EtOAc (2×30 mL). Theorganic layer was dried over anhydrous Na₂SO₄. After evaporation of thesolvents, the crude product was purified by MD Autoprep HPLC (Method B)to afford the title compound as off white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 7.58 (t, J=6.0 Hz, 1H), 7.39-7.32 (m, 4H), 6.86 (s, 1H),6.83 (d, J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.97-6.97 (m, 2H), 4.33(m, 2H), 3.32-3.21 (m, 1H), 3.19-3.16 (m, 4H), 2.43-2.21 (m, 4H), 1.25(d, J=6.4 Hz, 3H). LCMS: (Method B) 458.0 (M+H), Rt. 6.16 min, 96.93%(Max). HPLC: (Method A) Rt. 3.21 min, 96.02% (Max).

Example 1125-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethyl-1,3,4-thiadiazol-2-amine

The title compound was synthesized following the same procedure asExample 111, using acetaldehyde (0.17 mL, 1.35 mmol) as startingmaterial. After evaporation of the solvents, the crude product waspurified by flash chromatography to afford the title compound as offwhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ 6.99 (t, J=5.2 Hz, 1H), 6.88(d, J=1.2 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.74 (dd, J=7.6, 1.2 Hz, 1H),5.99-5.98 (m, 2H), 3.37 (d, J=6.4 Hz, 1H), 3.19-3.13 (m, 6H), 2.45-2.32(m, 4H), 1.25 (d, J=6.4 Hz, 3H), 1.11 (t, d, J=6.8 Hz, 3H). LCMS:(Method A) 362.0 (M+H), Rt. 2.01 min, 96.31% (Max). HPLC: (Method A) Rt.1.98 min, 94.56% (Max).

Example 1132-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of Intermediate 2 (0.3 g, 11.15 mmol) in dry NMP(3 mL), DIPEA (0.8 mL, 44.6 mmol) and2-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.17 g, 11.15 mmol) were added atrt and the reaction mixture was stirred at 220° C. for 6 h in microwave.It was cooled to rt and concentrated. The resulting mixture was dilutedwith EtOAc (30 mL), washed with water (10 mL) and dried over anhydrousNa₂SO₄. After evaporation of the solvents, the crude product which waspurified by MD Autoprep HPLC (Method B) to afford the title compound(off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.57 (s, 1H), 7.07 (t,J=2.8 Hz, 1H), 6.90 (s, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.76 (d, J=8 Hz,1H), 6.30 (m, 1H), 5.97 (dd, J=3.2 Hz, 2H), 3.67 (t, J=4.8 Hz, 4H),3.37-3.35 (m, 1H), 2.45-2.44 (m, 2H), 2.38-2.36 (m, 2H), 1.28 (d, J=76.4Hz, 3H). LCMS: (Method A) 352.2 (M+H), Rt2.10 min, 99.36% (Max). HPLC:(Method A) Rt. 2.01 min, 99.36% (Max).

Example 114N-(5-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of Intermediate 7 (0.5 g, 1.9 mmol) in DMF (5 mL),DIPEA (0.99 mL, 5.6 mmol) and Intermediate 17 (0.374 g, 1.9 mmol) wereadded at 0-5° C. The reaction mixture was stirred at 100° C. overnight.The completion of the reaction was confirmed by TLC. The reactionmixture was evaporated at 50° C. under reduced pressure and diluted withethyl acetate (30 mL). The organic layer washed with water (10 mL),brine solution (10 mL) and dried over Na₂SO₄. After evaporation of thesolvents, the crude product was purified by flash chromatography (5-8%MeOH in DCM) to give the title compound (pale brown solid). ¹H NMR (400MHz, DMSO-d₆): δ 12.01 (s, 1H), 9.38 (s, 1H), 8.11 (d, J=8.4 Hz, 1H),8.01 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 3.69-3.65 (m, 1H), 3.36-3.32 (m,4H), 2.58-2.50 (m, 2H), 2.50-2.43 (m, 2H), 2.08 (s, 3H), 1.39 (d, J=6.4Hz, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 2.17 min, 99.5% (Max). HPLC:(Method A) Rt 2.04 min, 99.2% (Max).

Example 115N-(5-(4-(1-(quinolin-7-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The title compound was synthesized according the protocol used forExample 114, using Intermediate 7 (0.39 g, 2.05 mmol) and Intermediate 9(0.5 g, 2.6 mmol) as starting materials. The crude product was purifiedby MD Autoprep (Method B) to afford title compound as white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 8.9 (dd, J=1.6, 4.4 Hz, 1H),8.35 (t, J=1.2 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.92 (s, 1H), 7.65 (dd,J=5.2, 6.8 Hz, 1H), 7.51 (dd, J=4.4, 8.4 Hz, 1H), 3.76-3.71 (m, 1H),3.39-3.35 (m, 4H), 2.62-2.58 (m, 2H), 2.48-2.45 (m, 2H), 2.09 (s, 3H),1.43 (d, J=6.8 Hz, 3H). LCMS: (Method B) 383.0 (M+H), Rt. 4.4 min, 96.3%(Max). HPLC: (Method B) Rt. 4.3 min, 95.4% (Max).

Example 116N-(2-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

The title compound was synthesized according the protocol used forExample 114, using Intermediate 10 (0.5 g, 1.9 mmol) and Intermediate 17(0.383 g, 1.9 mmol) as starting materials. The crude product waspurified by flash chromatography (7% MeOH in DCM) followed by MDAutoprep HPLC (Method B) to afford title compound (off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 9.81 (s, 1H), 9.38 (s, 1H), 8.46 (s, 1H), 8.11(d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.52-7.48 (m, 1H), 3.66-3.63 (m, 5H),2.52-2.50 (m, 2H), 2.40-2.37 (m, 2H), 2.00 (s, 3H), 1.40 (d, J=6.8 Hz,3H). LCMS: (Method A) 383.0 (M+H), Rt. 2.17 min, 93.53% (Max). HPLC:(Method A) Rt. 2.05 min, 94.64% (Max).

Example 117N-(5-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The title compound was synthesized according the protocol used forExample 114, using Intermediate 7 (0.5 g, 1.9 mmol) and Intermediate 18(0.418 g, 1.9 mmol). The crude product was purified by flashchromatography (5-8% MeOH in DCM) to give the title compound (pale brownsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.01 (s, 1H), 7.38-7.33 (m, 2H),7.15 (d, J=8.4 Hz, 1H), 3.55-3.51 (m, 1H), 3.35-3.32 (m, 4H), 2.56-2.42(m, 2H), 2.41-2.32 (m, 2H), 2.09 (s, 3H), 1.30 (d, J=8.0 Hz, 3H). LCMS:(Method A) 412.3 (M+H), Rt. 3.06 min, 99.3% (Max). HPLC: (Method A) Rt.2.98 min, 98.6% (Max).

Example 118N-(5-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The title compound was synthesized according the protocol used forExample 114, using Intermediate 10 (0.5 g, 1.9 mmol) and Intermediate 18(0.418 g, 1.9 mmol) as starting material. The crude product was purifiedby flash chromatography (5-8% MeOH in DCM) to give the title compound(pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.81 (s, 1H), 8.461 (s,2H), 7.38-7.32 (m, 2H), 7.16 (d, J=6.8 Hz, 1H), 3.63 (t, J=9.6 Hz, 4.8Hz, 4H), 3.50-3.47 (m, 1H), 2.50-2.43 (m, 2H), 2.36-2.32 (m, 2H), 1.99(s, 3H), 1.30 (d, J=6.8 Hz, 3H). LCMS: (Method A) 406.2 (M+H), Rt. 3.05min, 99.2% (Max). HPLC: (Method A) Rt. 2.98 min, 99.6% (Max).

Example 1192-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)quinazoline

To a stirred solution of Intermediate 2 (0.3 g, 1.28 mmol) in dry DMF(10 mL), TEA (1.5 mL, 1.09 mmol) and 2-chloroquinazoline (0.5 g, 2.74mmol) were added at rt and the resulting mixture was stirred at 80° C.for 12 h. It was cooled to rt, and concentrated. The crude residue wasdiluted with dichloromethane (50 mL), was washed with brine (10 mL), anddried over anhydrous Na₂SO₄. After evaporation of the solvents, thecrude product was purified by MD Autoprep HPLC (Method B) (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): 9.17 (s, 1H), 7.81 (d, J=7.6 Hz, 1H),7.70 (t, J=8.0 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H),6.90 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.98 (d,J=2.4 Hz, 2H), 3.83 (t, J=5.6 Hz, 4H), 3.38 (t, J=6.0 Hz, 1H), 2.37-2.40(m, 4H), 1.23 (d, J=2.4 Hz, 3H), LCMS: (Method A) 363.3 (M+H), Rt. 2.94min, 99.0% (Max). HPLC: (Method A) Rt. 2.95 min, 98.5% (Max).

Example 120N-(2-(4-(1-(quinolin-7-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

To a stirred solution of Intermediate 10 (0.72 g, 2.80 mmol) in dry ACN(10 mL), DIPEA (2 mL, 11.20 mmol) and Intermediate 9 (0.54 g, 2.80 mmol)were added at rt and the reaction mixture was stirred overnight at 80°C. It was cooled to rt and concentrated. The resulting mixture wasdiluted with EtOAc (50 mL), washed with water (15 mL) and dried overanhydrous Na₂SO₄. After evaporation of the solvents, the crude productwas purified by flash column chromatography to afford the title compound(brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.81 (s, 1H), 8.89-8.88 (m,1H), 8.46 (s, 2H), 8.34 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.91(s, 1H), 7.67-7.65 (m, 1H), 7.51-7.50 (m, 1H), 3.67-3.66 (m, 5H),2.51-2.50 (m, 2H), 2.42-2.40 (m, 2H), 2.02 (s, 3H), 1.42 (d, J=6.8 Hz,3H). LCMS: (Method A) 377.2 (M+H), Rt. 1.42 min, 99.10% (Max). HPLC:(Method A) Rt. 1.40 min, 96.61% (Max).

Example 121N-(2-(4-(1-(benzo[c][1,2,5]oxadiazol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

To a stirred solution of Intermediate 10 (0.59 g, 2.68 mmol) in dry DMF(10 mL), TEA (1.4 mL, 10.7 mmol) and Intermediate 13 (0.5 g, 2.68 mmol)were added at rt and the reaction mixture was stirred at 90° C. for 12h. It was cooled to rt and concentrated. The crude product was dilutedwith dichloromethane (50 mL), washed with brine (10 mL) and dried overanhydrous Na₂SO₄. After evaporation of the solvents, the crude productwas purified by MD Autoprep HPLC (Method B) (off white solid). ¹H NMR(400 MHz, DMSO-d6): 9.83 (s, 2H), 8.48 (s, 2H), 7.90 (s, 1H), 7.71 (dd,J=1.2, 9.2 Hz, 1H), 3.63-3.68 (m, 5H), 2.39-2.50 (m, 4H), 2.01 (s, 3H),1.37 (d, J=6.4 Hz, 3H), LCMS: (Method A) 368.0 (M+H), Rt. 2.08 min,98.5% (Max). HPLC: (Method A) Rt. 2.05 min, 95.9% (Max).

Example 122N-(2-(4-(1-(benzo[c][1,2,5]thiadiazol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

The title compound was synthesized according the protocol used forExample 114, using Intermediate 10 (0.3 g, 1.16 mmol) and Intermediate19 (0.323 g, 1.6 mmol) as starting material. The crude product waspurified by flash chromatography (7% MeOH in DCM) and then againpurified by MD Autoprep HPLC (Method C) to give the title compound (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.81 (s, 1H), 8.46 (s, 2H),8.05 (d, J=8.8 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 3.69-3.65(m, 5H), 2.55-2.53 (m, 2H), 2.43-2.38 (m, 2H), 1.99 (s, 3H), 1.40 (d,J=6.4 Hz, 3H). LCMS: (Method A) 384.2 (M+H), Rt. 2.20 min, 97.23% (Max).HPLC: (Method A) Rt. 2.13 min, 98.37% (Max).

Example 123N-(5-(4-(1-(benzo[c][1,2,5]thiadiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The title compound was synthesized according the protocol used forExample 114, using Intermediate 7 (0.5 g, 1.8 mmol) and Intermediate 19(0.527 g, 2.65 mmol) as starting materials. The crude product waspurified by flash chromatography (7% MeOH in DCM) to give the titlecompound (pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H),8.05 (d, J=9.2 Hz, 1H), 7.98 (s, 1H), 7.80 (dd, J=9.2, 1.2 Hz, 1H),3.77-3.72 (m, 1H), 3.39-3.34 (m, 4H), 2.63-2.59 (m, 2H), 2.53-2.46 (m,2H), 2.09 (s, 3H), 1.41 (d, J=6.4 Hz, 3H). LCMS: (Method A) 390.0 (M+H),Rt. 2.19 min, 99.17% (Max). HPLC: (Method A) Rt. 2.13 min, 98.91% (Max).

Example 124N-(5-(4-(1-(benzo[c][1,2,5]thiadiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The title compound was synthesized according the protocol used forExample 114, using Intermediate 7 (0.250 g, 0.9 mmol) and Intermediate20 (0.30 g, 1.3 mmol) as starting materials. The crude product waspurified by flash chromatography (7% MeOH in DCM) to give the titlecompound (pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (s, 1H),8.88-8.87 (m, 1H), 8.56-8.55 (m, 1H), 7.98-7.95 (m, 2H), 7.72 (d, J=8.4Hz, 1H), 3.75 (q, J=6.8 Hz, 1H), 3.37 (t, J=4.4 Hz, 4H), 2.61-2.58 (m,2H), 2.51-2.45 (m, 2H), 2.09 (s, 3H), 1.41 (d, J=6.8 Hz, 3H). LCMS:(Method A) 417.0 (M+H), Rt. 2.65 min, 98.42% (Max). HPLC: (Method A) Rt.2.58 min, 98.73% (Max).

Example 125N-(2-(4-(1-(3-chloroquinolin-7-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

The title compound was synthesized according the protocol used forExample 114, using Intermediate 10 (0.250 g, 0.9 mmol) and Intermediate20 (0.307 g, 1.3 mmol) as starting materials. The crude product waspurified by MD Autoprep HPLC (Method B) to give the title compound (palebrown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.81 (s, 1H), 8.87 (d, J=2.4Hz, 1H), 8.55 (d, J=2.4 Hz, 1H), 8.46 (s, 2H), 7.97-7.95 (m, 2H), 7.73(d, J=7.6 Hz, 1H), 3.70-3.65 (m, 5H), 2.50-2.41 (m, 2H), 2.42-2.37 (m,2H), 2.00 (s, 3H), 1.41 (d, J=6.4 Hz, 3H). LCMS: (Method A) 411.2 (M+H),Rt. 2.60 min, 99.12% (Max). HPLC: (Method A) Rt. 2.59 min, 98.33% (Max).

Example 126N-(2-(4-(1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

The title compound was synthesized according the same protocol asdescribed for the synthesis of Example 121, using Intermediate 14 andIntermediate 10 as starting materials. The crude product was purified byMD Autoprep HPLC (Method C) (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 9.80 (s, 1H), 8.45 (s, 2H), 6.88 (d, J=4.8 Hz, 3H),4.10-4.08 (m, 3H), 337-3.38 (m, 2H), 3.32-3.29 (m, 4H), 2.49-2.48 (m,2H), 2.46-2.44 (m, 2H), 2.07-2.01 (m, 2H), 1.99 (s, 3H), 1.24 (d, J=6.4Hz, 3H). LCMS: (Method A) 397.3 (M+H), Rt. 2.43 min, 98.43% (Max). HPLC:(Method A) Rt. 2.41 min, 97.8% (Max).

Example 127N-(2-(4-(1-(quinolin-8-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

To a stirred solution of Intermediate 10 (0.4 g, 1.57 mmol) in dry DMF(10 mL), DIPEA (0.8 mL, 3.13 mmol) and Intermediate 15 (0.3 g, 1.57mmol) were added at rt and the resulting reaction mixture was stirred at80° C. for 12 h. It was cooled to rt and concentrated. The crude productwas diluted with dichloromethane (50 mL), washed with brine (10 mL) anddried over anhydrous Na₂SO₄. After evaporation of the solvents, thecrude product was purified by flash column chromatography to afford thetitle compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.81 (s,1H), 8.91 (dd, J=4.0, 1.6 Hz, 1H), 8.46 (s, 2H), 8.37 (dd, J=8.0, 1.6Hz, 1H), 7.92 (d, J=6.8 Hz 1H), 7.86 (d, J=8.0 Hz, 1H), 7.66-7.62 (m,1H), 7.54 (dd, J=8.0, 4.0 Hz, 1H), 4.98 (q, J=6.4 Hz, 1H), 3.66-3.65 (m,4H), 2.57-2.42 (m, 4H), 2.01 (s, 3H), 1.38 (d, J=6.4 Hz, 3H). LCMS:(Method A) 377.2 (M+H), Rt. 2.47 min, 98.0% (Max). HPLC: (Method A) Rt.2.43 min, 97.5% (Max).

Example 128N-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The title compound was synthesized according the protocol used forExample 114, using Intermediate 7 (0.3 g, 1.14 mmol) and Intermediate 21(0.269 g, 1.48 mmol) as starting materials. The crude product waspurified by flash chromatography (7% MeOH in DCM) followed by MDAutoprep HPLC (Method B) to give the title compound (off white solid).¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (s, 1H), 7.12 (d, J=7.2 Hz, 1H), 6.76(d, J=87.6 Hz, 1H), 6.71 (s, 1H), 4.51 (t, J=8.4 Hz, 2H), 3.39-3.28 (m,5H), 3.14 (t, J=8.4 Hz, 2H), 2.42-2.39 (m, 4H), 2.09 (s, 3H), 1.28 (d,J=6.4 Hz, 3H). LCMS: (Method A) 374.2 (M+H), Rt. 2.34 min, 99.62% (Max).HPLC: (Method A) Rt. 2.32 min, 96.03% (Max).

Example 129N-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

The title compound was synthesized according the protocol used forExample 114, using Intermediate 10 (0.3 g, 1.16 mmol) and Intermediate21 (0.274 g, 1.51 mmol) as starting materials. The crude product waspurified by flash chromatography (10% MeOH in DCM) followed by MDAutoprep HPLC (Method B) to give the title compound (off white solid).¹H NMR (400 MHz, DMSO-d₆): δ 9.80 (s, 1H), 8.45 (s, 2H), 7.13 (d, J=7.6Hz, 1H), 6.75-6.70 (m, 1H), 4.49 (t, J=8.4 Hz, 2H), 3.63-3.61 (m, 4H),3.12 (t, J=8.4 Hz, 3H), 2.44-2.30 (m, 4H), 1.99 (s, 3H), 1.26 (d, J=6.4Hz, 3H). LCMS: (Method A) 368.3 (M+H), Rt. 2.34 min, 99.74% (Max). HPLC:(Method A) Rt. 2.33 min, 99.52% (Max).

Example 1302-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)benzo[d]thiazole

To a stirred solution of Intermediate 2 (0.5 g, 2.13 mmol) in dry DMF(10 mL), DIPEA (0.8 mL, 6.3 mmol) and 2-bromo benzothiazole (0.5 g, 2.13mmol) were added at rt and the reaction mixture was stirred at 90° C.for 12 h. It was cooled to rt and concentrated. The crude product wasdiluted with dichloromethane (50 mL), washed with brine (10 mL) anddried over anhydrous Na₂SO₄. After evaporation of the solvents, thecrude product was purified by flash chromatography to give the titlecompound. ¹H NMR (400 MHz, DMSO-d₆): δ 7.74 (d, J=0.8 Hz, 1H), 7.43 (d,J=7.6 Hz, 1H), 7.28-7.24 (m, 1H), 7.09-7.04 (m, 1H), 6.91 (d, J=1.6 Hz,1H), 6.83 (d, J=8 Hz, 1H), 6.86-6.73 (m, 1H), 5.91 (d, J=1.6 Hz, 2H),3.56-3.51 (m, 4H), 3.44-3.36 (m, 1H), 2.47-2.41 (m, 4H), 1.28 (d, J=6.8Hz, 3H). LCMS: (Method A) 368.2 (M+H), Rt. 3.34 min, 95.18% (Max). HPLC:(Method A) Rt. 3.34 min, 97.15% (Max).

Example 131N-(2-(4-(1-(quinolin-3-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

To a stirred solution of Intermediate 10 (0.5 g, 1.9 mmol) in DMF (5mL), DIPEA (1.65 mL, 9.5 mmol) and Intermediate 23 (0.496 g, 2.59 mmol)were added at 0-5° C. The reaction mixture was stirred at 100° C.overnight. It was then concentrated under reduced pressure. The crudeproduct was diluted with DCM (100 mL), washed with water (2×25 mL) anddried over Na₂SO₄. After evaporation of the solvents, the crude productwas purified by flash chromatography (7% MeOH in DCM). It was trituratedwith ACN (5 mL) and diethyl ether (2×15 mL) to give the title compoundas pale brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.81 (s, 1H),8.93-8.91 (m, 1H), 8.459 (s, 2H), 8.24-8.22 (m, 1H), 7.99 (t, J=8.0 Hz,2H), 7.73-7.71 (m, 1H), 7.60-7.58 (m, 1H), 3.79-3.73 (m, 1H), 3.67-3.65(m, 4H), 2.55-2.50 (m, 2H), 2.50-2.40 (m, 2H), 2.02 (s, 3H), 1.44 (d,J=6.4 Hz, 3H). LCMS: (Method A) 377.2 (M+H), Rt. 1.80 min, 94.43% (Max).HPLC: (Method A) Rt. 1.82 min, 94.95% (Max).

Example 132(S)-5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-amine

To a stirred solution of Intermediate 16 (3 g, 11.1 mmol) in ACN (30mL), TEA (3.36 g, 33.3 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (2.19g, 12.2 mmol) were added at rt and the mixture was heated at 85° C.overnight. The completion of the reaction was confirmed by TLC. Thereaction mixture was evaporated under vacuum and the resulting crudesolid was diluted with water (30 mL) and extracted with EtOAc (3×30 mL).The combined organic layer was washed with brine (30 mL), dried overNa₂SO₄ and evaporated at 45° C. under vacuum. The crude product waspurified by flash chromatography (7% MeOH in DCM) to give the titlecompound (pale brown solid). ¹H NMR (400 MHz, DMSO-d6): δ 6.88-6.83 (m,2H), 6.76-6.74 (m, 1H), 6.46 (s, 2H), 5.91 (d, J=1.6 Hz, 2H), 3.39-3.37(m, 1H), 3.20-3.17 (m, 4H), 2.46-2.30 (m, 4H), 1.25 (d, J=6.5 Hz, 3H).LCMS: (Method A) 334.0 (M+H), Rt. 1.85 min, 96.47% (Max). HPLC: (MethodA) Rt. 1.79 min, 96.77% (Max). Chiral HPLC: (Method D) Rt. 20.96 min,100.00%

Example 133(S)-N-(5-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamideor((R)-N-(5-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The two enantiomers of Example 114 were separated by chiral preparativeHPLC (Method PF). Example 133 corresponds to the second eluting fraction(off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.01 (s, 1H), 9.34 (s,1H), 8.12 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 3.67(d, J=6.0 Hz, 1H), 3.37-3.35 (m, 4H), 2.56-2.57 (m, 4H), 2.09 (s, 3H),1.40 (d, J=6.8 Hz, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 2.09 min,96.5% (Max). HPLC: (Method A) Rt. 2.08 min, 97.4% (Max). Chiral HPLC:(Method D) Rt 15.28 min, 99.82%.

Example 134 (S)2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

Step 1: Ethyl(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a stirred solution of Intermediate 16 (1.87 g, 6.94 mmol) in dryacetonitrile (10 mL), potassium carbonate (2.87 g, 20.8 mmol,Spectrochem) and ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (1.6g, 6.94 mmol, synthesis described in Example 98, steps, 1 and 2) wereadded. The resulting mixture was stirred at rt for 3 h. It was thenfiltered through celite and concentrated. The crude product was dilutedwith dichloromethane (25 mL), washed with water and dried over anhydrousNa₂SO₄. After evaporation of the solvent, the crude product was purifiedby flash column chromatography to afford the title compound (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.74 (s, 1H), 6.78-6.72 (m, 2H),5.97 (s, 1H), 4.38-4.36 (m, 1H), 3.81 (s, 2H), 2.37-2.47 (m, 9H), 1.26(d, J=2.84 Hz, 3H), LCMS: (Method A) 385.2 (M+H), Rt. 3.22 min, 98.6%(Max).

Step 2: Lithium(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a stirred solution of ethyl(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate(1.6 g, 17.5 mmol) in a mixture of MeOH (2 mL), THF (7 mL) and water (1mL), lithium hydroxide (0.431 g, 5.20 mmol, Spectrochem) was added at 0°C. and the resulting mixture was stirred at rt for 12 h. It wasconcentrated and the resulting product was taken for next step withoutany further purification. Yield: 96% (0.61 g, off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.61 (s, 1H), 6.81-6.88 (m, 4H), 5.97 (d, J=1.8Hz, 2H), 3.68 (d, J=6.2 Hz, 2H), 3.22-3.21 (m, 1H), 2.28-2.35 (m, 6H),1.26 (d, J=8.9 Hz, 3H), LCMS: (Method A) 357.0 (M+H), Rt. 2.41 min,97.1% (Max)

Step 3: (S)2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

To a stirred solution of lithium(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate(0.3 g, 0.82 mmol) in dry DCM (10 mL), triethylamine (0.34 mL) andmethylamine in THF (2 M, 1.6 mL, 3.32 mmol) were added at 0° C. Thereaction mixture was stirred at rt for 1 h. The reaction progression wasmonitored by TLC. After completion of the reaction, the mixture wasdiluted with 10% sodium bicarbonate solution (10 mL) and extracted withDCM (20 mL). The organic layer was dried over Na₂SO₄ and evaporated todryness. The crude product was purified by flash column chromatography.Yield: 56% (0.17 g, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.71(s, 2H), 8.28 (d, J=4.8 Hz, 1H), 6.90-6.83 (m, 2H), 6.77-6.75 (m, 1H),5.98 (d, J=2.0 Hz, 2H), 3.77 (t, J=4.8 Hz, 4H), 3.41-3.38 (m, 1H), 2.74(d, J=4.4 Hz, 3H), 2.38-2.33 (m, 4H), 1.28 (d, J=6.8 Hz, 3H). LCMS:(Method A) 370.2 (M+H), Rt. 2.21 min, 98.9% (Max). HPLC: (Method A) Rt.2.18 min, 99.3% (Max). Chiral HPLC: (Method G) Rt. 5.51 min, 100.00%

Example 1352-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)benzo[d]thiazole

To a stirred solution of Intermediate 11 (0.26 g, 0.93 mmol) in dry DMF(3 mL), TEA (0.4 mL, 2.81 mmol) and 2-bromobenzothiazole (0.2 g, 0.93mmol, combi blocks) were added at rt and the reaction mixture wasstirred overnight at 95° C. It was cooled to rt and concentrated. To theresulting mixture, water (20 mL) was added and the product was extractedwith EtOAc (2×40 mL). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated. The crude product was purified byflash column chromatography to afford the title compound (brown solid).¹H NMR (400 MHz, DMSO-d₆): δ 8.92 (d, J=4.0 Hz, 2H), 8.09 (d, J=8.8 Hz,1H), 8.01 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.42(d, J=8.0 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H),3.83-3.81 (m, 1H), 3.56 (t, J=4.8 Hz, 4H), 2.64-2.63 (m, 2H), 2.49 (m,2H), 1.44 (d, J=6.8 Hz, 3H). LCMS: (Method A) 376.3 (M+H), Rt. 2.71 min,99.382% (Max). HPLC: (Method A) Rt. 2.69 min, 98.44% (Max).

Example 136(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)benzo[d]thiazole

To a stirred solution of Intermediate 16 (0.3 g, 1.27 mmol) in dry DMF(10 mL), TEA (0.67 mL, 3.82 mmol) and 2-bromo benzothiazole (0.27 g,1.27 mmol) were added at rt and the reaction mixture was stirred at 90°C. for 12 h. It was cooled to rt, concentrated. The resulting mixturewas diluted with dichloromethane (50 ml), washed with brine (10 ml) anddried over anhydrous Na₂SO₄. After evaporation of the solvents, thecrude product was purified by flash chromatography to give the titlecompound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.74 (d, J=7.6Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.27 (t, 1H), 7.05 (t, J=7.6 Hz, 1H),6.90 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 5.91 (d,J=1.6 Hz, 2H), 3.53 (t, J=7.6 Hz, 4H), 3.44-3.38 (m, 1H), 2.47-2.44 (m,4H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 368.0 (M+H), Rt. 3.28 min,96.86% (Max). HPLC: (Method A) Rt. 3.33 min, 97.08% (Max). Chiral HPLC:(Method G) Rt. 8.00 min, 100.00%

Example 137(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylpyrimidine-5-carboxamide

The title compound was synthesized using the same procedure as describedfor Example 134, using lithium(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylateand N,N-dimethyl amine as solution in THF as starting materials. Thecrude product was purified by flash column chromatography (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.45 (s, 2H), 6.90 (s, 1H), 6.84(d, J=8.0 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 5.98 (d, J=1.6 Hz, 2H), 3.76(t, J=4.8 Hz, 4H), 3.39-3.37 (m, 1H), 2.97 (s, 6H), 2.44-2.43 (m, 2H),2.37-2.35 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 384.2 (M+H),Rt. 2.44 min, 98.2% (Max). HPLC: (Method A) Rt. 2.44 min, 98.3% (Max).Chiral HPLC: (Method G) Rt. 6.98 min, 100.00%

Example 138(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1H-benzo[d]imidazole

To a stirred solution of Intermediate 13 (0.25 g, 0.92 mmol) in dry DMF(3 mL), TEA (0.5 mL, 3.71 mmol) and 2-bromo-1H-benzoimidazole (0.18 g,0.92 mmol, Arbor chemicals) were added at rt and the reaction mixturewas stirred at 100° C. overnight. It was cooled to rt and concentrated.This crude product was purified by flash column chromatography to affordthe title compound (brown solid). ¹H NMR (400 MHz, CDCl₃): δ 7.33 (m,2H), 7.07-7.06 (m, 2H), 6.86 (d, J=1.2 Hz, 1H), 6.76-6.74 (m, 2H),5.97-5.96 (m, 2H), 3.59-3.58 (m, 4H), 3.35-3.34 (m, 1H), 2.60-2.59 (m,2H), 2.52-2.51 (m, 2H), 1.35 (d, J=8.0 Hz, 3H). LCMS: (Method A) 351.2(M+H), Rt. 2.29 min, 95.81% (Max). HPLC: (Method A) Rt. 2.19 min, 96.33%(Max).

Example 139(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazolo[4,5-c]pyridine

To a stirred solution of Intermediate 13 (0.189 g, 0.64 mmol) in dry DMF(5 mL), TEA (0.23 mL, 1.75 mmol) and 2-chlorothiazolo[4,5-C]pyridine(0.1 g, 0.58 mmol) were added at rt and the reaction mixture was stirredovernight at 100° C. It was cooled to rt and concentrated under vacuum.To this crude residue, water (5 mL) was added and extracted with EtOAc(2×25 mL). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated. The crude product was purified by flash columnchromatography to afford the title compound (off white solid). ¹H NMR(400 MHz, DMSO-d₆): 1HNMR (400 MHz, DMSO-d6): δ 8.66 (s, 1H), 8.18 (d,J=5.2 Hz, 1H), 7.84 (d, J=5.2 Hz, 1H), 6.91 (d, J=1.2 Hz, 1H), 6.85 (d,J=8.0 Hz, 1H), 6.77 (d, J=8.0, 1.2 Hz, 1H), 5.60-5.99 (m, 2H), 3.59-3.57(m, 2H), 3.45 (q, J=6.8 Hz, 1H), 2.51-2.46 (m, 4H), 1.29 (d, J=6.8 Hz,3H). LCMS: (Method A) 369.0 (M+H), Rt. 1.90 min, 99.501% (Max). HPLC:(Method A) Rt. 1.82 min, 99.73% (Max). Chiral HPLC: (Method G) Rt. 8.31min, 100.00%

Example 1402-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)thiazolo[4,5-c]pyridine

To a stirred solution of Intermediate 11 (0.169 g, 0.58 mmol) in dry DMF(5 mL), TEA (0.23 mL, 1.75 mmol) and 2-chlorothiazolo[4,5-C]pyridine(0.18 g, 0.60 mmol) were added at rt and the reaction mixture wasstirred overnight at 100° C. The reaction mixture was cooled to rt andconcentrated under vacuum. To the crude residue, water (5 mL) was addedand extracted with EtOAc (2×25 mL). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated. The crude product waspurified by MD Autoprep HPLC (Method B) to afford the title compound(off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (d, J=7.2 Hz, 1H),8.92 (d, J=7.2 Hz, 1H), 8.65 (s, 1H), 7.16 (d, J=5.2 Hz, 1H), 8.09 (d,J=8.4 Hz, 1H), 7.91 (dd, J=8.3, 2.0 Hz, 1H), 7.83 (d, J=5.4 Hz, 1H),3.84 (q, J=6.8 Hz, 1H), 3.62-3.60, 2.61-2.48 (m, 4H), 1.29 (d, J=6.8 Hz,3H). LCMS: (Method A) 377.2 (M+H), Rt. 1.48 min, 99.79% (Max). HPLC:(Method A) Rt. 1.481 min, 99.10% (Max).

Example 141(S)-5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethyl-1,3,4-thiadiazol-2-amine

To a stirred solution of Example 132 (0.7 g, 2.1 mmol) in THF (14 mL),acetaldehyde (0.84 mL, 5M in THF) and titanium(IV)ethoxide (0.958 g, 4.2mmol) were added and the resulting mixture was stirred at rt overnight.The completion of the reaction was confirmed by TLC. The reactionmixture was cooled to 0° C. and sodium borohydride (0.238 g, 6.3 mmol)was added. The reaction mixture was stirred 2 h at rt. It was quenchedwith water (10 mL) and filtered through celite. The celite bed washedwith EtOAc (2×50 mL) and the filtrate was washed with water (10 mL),brine (10 mL), dried over Na₂SO₄. It was evaporated at 50° C. undervacuum. The crude product was purified by MD Autoprep HPLC (Method D) togive the title compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ6.98 (t, J=5.2 Hz, 2H), 6.88 (d, J=1.2 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H),6.75 (dd, J=8.0, 1.2 Hz, 1H), 5.99-5.98 (m, 2H), 3.37 (q, J=6.8 Hz, 2H),3.20-3.14 (m, 6H), 2.47-2.36 (m, 4H), 1.26 (d, J=6.8 Hz, 3H), 1.11 (t,J=7.2 Hz, 3H). LCMS: (Method A) 362.0 (M+H), Rt. 2.01 min, 99.75% (Max).HPLC: (Method A) Rt. 2.02 min, 97.69% (Max). Chiral HPLC: (Method B) Rt.3.90 min, 100%

Example 142(S)-5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-propyl-1,3,4-thiadiazol-2-amine

To a stirred solution of Example 132 (0.5 g, 1.5 mmol) in THF (10 mL),propionaldehyde (0.17 g, 3.0) and titanium(IV)ethoxide (0.684 g, 3.0mmol) were added at rt and stirred overnight. The completion of thereaction was confirmed by TLC. The reaction mixture was cooled to 0° C.and sodium borohydride (0.17 g, 4.4 mmol) was added. The reactionmixture was stirred for 2 h at rt. It was quenched with water (10 mL)and filtered through celite. The celite bed washed with EtOAc (2×50 mL)and the filtrate was washed with water (10 mL), brine solution (10 mL)and dried over Na₂SO₄. It was evaporated at 50° C. under vacuum. Thecrude product was purified by MD Autoprep HPLC (Method D) to give thetitle compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.02 (t,J=5.2 Hz, 2H), 6.88 (d, J=1.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (dd,J=7.6, 1.6 Hz, 1H), 5.99-5.98 (m, 2H), 3.41 (q, J=6.4 Hz, 2H), 3.20-3.17(m, 4H), 3.11-3.06 (m, 2H), 2.45-2.32 (m, 4H), 1.56-1.47 (m, 2H), 1.26(d, J=6.4 Hz, 3H), 0.86 (t, J=7.6 Hz, 3H). LCMS: (Method A) 376.0.0(M+H), Rt. 2.23 min, 99.08% (Max). HPLC: (Method A) Rt. 2.21 min, 97.11%(Max). Chiral HPLC: (Method B) Rt. 3.61. min, 100%.

Example 143(R)-5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-amine

To a stirred solution of Intermediate 24 (1 g, 4.27 mmol) in ACN (10mL), TEA (1.75 mL, 12.8 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine(0.764 g, 4.27 mmol) were added at rt and the resulting mixture washeated at 85° C. overnight. Completion of the reaction was confirmed byTLC. Reaction mixture was evaporated under vacuum. To the resultingcrude solid, water (50 mL) was added and stirred for 15 min. Then thereaction mixture was filtered and filtration cake was washed with water(20 mL) and pet ether (2×20 mL). The crude product was triturated withEt₂O (2×20 mL), filtered and dried under vacuum. The title compound wasisolated as brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ 6.88-6.83 (m, 2H),6.76-6.74 (m, 1H), 6.46 (s, 2H), 5.99-5.97 (m, 2H), 3.36 (m, 1H),3.20-3.17 (m, 4H), 2.50-2.33 (m, 4H), 1.26 (d, J=6.8 Hz, 3H). LCMS:(Method A) 334.0 (M+H), Rt. 1.82 min, 94.96% (Max). HPLC: (Method A) Rt.1.81 min, 93.22% (Max). Chiral HPLC: (Method A) Rt. 18.36 min, 97.38%.

Example 1442-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylthiazole

Step 1: tert-Butyl 4-(4-methylthiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 1.0 g, 4.08 mmol) in dioxane (10 mL), TEA (0.58 g,5.3 mmol) and bromo acetone (0.67 mL, 5.3 mmol) were added at rt and theresulting mixture was stirred at 90° C. for 16 h. The completion of thereaction was monitored by TLC. The reaction mixture was diluted withwater (10 mL) and extracted with EtOAc (2×25 mL). The organic layer wasdried over anhydrous Na₂SO₄, concentrated under vacuum. The crudeproduct was taken as such for next step. Yield: 77% (0.9 g, pale yellowsolid). LCMS: (Method A) 284.0 (M+H), Rt. 2.74 min, 83.2% (Max).

Step 2: 4-Methyl-2-(piperazin-1-yl)thiazole hydrochloride

To a stirred solution of tert-butyl4-(4-methylthiazol-2-yl)piperazine-1-carboxylate (1.0 g, 3.53 mmol) indry dioxane (2 mL), HCl in dioxane (4 N, 10 mL) was added at rt and theresulting mixture was stirred for 3 h. It was concentrated under vacuumand the resulting crude product was triturated in Et₂O, filtrated anddried under vacuum to afford the title compound. Yield: 75% (500 mg, offwhite solid).

Step 3:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylthiazole

The title compound was synthesized by following general procedure D,using 4-methyl-2-(piperazin-1-yl)thiazole hydrochloride (1.01 g, 5.41mmol) and Intermediate 1 (1.0 g, 5.41 mmol). The crude product waspurified by flash chromatography (1.2-1.5% MeOH in DCM) to afford thetitle compound (colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 6.88 (s,1H), 6.83 (d, J=8.0 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.34 (s, 1H), 5.97(s, 2H), 3.39-3.37 (m, 1H), 3.32-3.29 (m, 4H), 2.46-2.43 (m, 2H),2.41-2.37 (m, 2H), 2.10 (s, 1H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (MethodA) 332.0 (M+H), Rt. 2.04 min, 99.1% (Max). HPLC: (Method A) Rt. 2.02min, 99.6% (Max).

Example 1482-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

To a stirred solution of Intermediate 25 (0.75 g, 2.43 mmol) in dry DMF(7 mL), TEA (1.4 mL, 7.30 mmol) and Intermediate 1 (0.9 g, 4.87 mmol)were added at rt. The resulting mixture was stirred overnight at 120° C.It was cooled to rt and DMF was evaporated under reduced pressure.Resulting crude product was purified by flash column chromatographyfollowed by MD Autoprep HPLC (Method B), affording the title product(off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.32 (s, 1H), 6.86-6.84(m, 3H), 5.99-5.98 (m, 2H), 3.45-3.44 (m, 4H), 3.38-3.34 (m, 2H),2.70-2.67 (m, 2H), 2.50-2.59 (m, 4H), 1.28-1.23 (m, 3H). LCMS: (MethodA) 387.2 (M+H), Rt. 2.15 min, 96.71% (Max). HPLC: (Method A) Rt. 2.11min, 94.32% (Max).

Example 1656-(1-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethyl)quinoxaline

To a stirred solution of Intermediate 11 (0.3 g, 1.23 mmol) in dry DMF(5 mL), TEA (0.5 mL, 3.71 mmol) and 2-chloro-5(trifluoromethyl) pyridine(0.22 g, 1.23 mmol) were added at rt. The resulting mixture was stirredat 90° C. overnight. It was cooled to rt and solvents were evaporated.Water (20 mL) was added and the desired product was extracted with EtOAc(2×30 mL). The resulting organic layer was dried over Na₂SO₄ andconcentrated. The crude product was purified by flash columnchromatography, affording the title compound (brown oil). ¹H NMR (400MHz, DMSO-d₆): δ 8.94-8.93 (m, 2H), 8.38 (s, 1H), 8.09 (d, J=8.8 Hz,1H), 8.01 (s, 1H), 7.93-7.91 (m, 1H), 7.77-7.75 (m, 1H), 6.91 (d, J=9.2Hz, 1H), 3.78-3.77 (m, 1H), 3.62 (m, 4H), 2.58-2.57 (m, 2H), 2.46-2.44(m, 2H), 1.44 (d, J=6.8 Hz, 3H). LCMS: (Method A) 388.0 (M+H), Rt. 3.17min, 97.92% (Max). HPLC: (Method A) Rt 3.10 min, 96.45% (Max).

Example 166(S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine

To a stirred solution of Intermediate 16 (0.25 g, 0.93 mmol) in dry DMF(5 mL), TEA (0.4 mL, 2.7 mmol) and 2-chloro-5-fluoro methyl pyridine(0.16 g, 9.3 mmol) were added at rt. The resulting reaction mixture wasstirred at 90° C. for 12 h. It was cooled to rt, concentrated anddiluted with dichloromethane (30 mL). The resulting solution was washedwith saturated NaCl solution (10 mL), dried over anhydrous Na₂SO₄ andconcentrated. The resulting crude product was purified by flashchromatography affording the title compound (brown oil). ¹H NMR (400MHz, DMSO-d₆): δ 8.38 (s, 1H), 7.78 (dd, J=9.2, 2.4 Hz, 1H), 6.88 (d,J=8.0 Hz, 2H), 6.84 (d, J=8.0 Hz, 1H), 6.77-6.75 (m, 1H), 5.99-5.98 (m,2H), 3.60 (t, J=4.8 Hz, 4H), 3.40-3.37 (m, 1H), 2.48-2.44 (m, 4H), 1.27(d, J=6.4 Hz, 3H). LCMS: (Method A) 380.0 (M+H), Rt. 3.73 min, 98.89%(Max). HPLC: (Method A) Rt. 3.67 min, 99.06% (Max).

Example 167(S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-one

Step 1: 1-(2-chloropyrimidin-5-yl)ethan-1-one

5-Bromo 2-chloro pyrimidine (2 g, 10.33 mmol, Combi-Blocks) was degassedfor 30 min. 1-Ethoxy vinyl tributyltin (4.1 mL, 11.3 mmol, FrontierScientific) and bis(triphenylphosphine)palladium dichloride (0.36 g,0.51 mmol) were added at rt. The resulting mixture was stirred overnightat 90° C. It was cooled to rt and filtered through celite. An aqueousHCl solution (6 N, 10 mL) was added and the mixture was stirred for 1hour at rt. It was neutralized with sat.NaHCO₃ solution (15 mL),extracted with DCM (50 mL), dried over anhydrous Na₂SO₄ andconcentrated. The crude product was purified by flash columnchromatography to afford the title compound (pale yellow solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.90 (s, 2H), 2.65 (s, 3H). LCMS: (Method B) 162.0(M+H), Rt. 4.6 min, 98.01% (Max).

Step 2:(S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-one

To a stirred solution of Intermediate 16 (1.14 g, 4.24 mmol) in dry DMF(10 mL), TEA (1.1 mL, 16.5 mmol) and1-(2-chloropyrimidin-5-yl)ethan-1-one obtained in the previous step (0.6g, 3.85 mmol) were added at rt. The resulting mixture was heated to 90°C. for 12 h. It was cooled to rt and concentrated. Dichloromethane (50mL) was added and was washed with a saturated NaCl solution (10 mL),dried over anhydrous Na₂SO₄ and concentrated. The crude product waspurified by flash chromatography, affording the title compound (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.83 (s, 2H), 6.90 (s, 1H),6.84 (d, J=7.6 Hz, 1H), 6.74 (dd, J=8.0, 1.2 Hz, 1H), 5.99-5.98 (m, 2H),3.84 (t, J=4.8 Hz, 4H), 3.40-3.36 (m, 1H), 2.49-2.47 (m, 5H), 2.38-2.35(m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 355.0 (M+H), Rt. 2.61min, 99.78% (Max). HPLC: (Method A) Rt. 2.55 min, 99.51% (Max).

Example 1681-(2-(4-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol

To a stirred solution of Example 167 (0.2 g, 0.56 mmol) in dry MeOH (5mL), sodium borohydride (0.48 g, 0.84 mmol, spectrochem) was addedportion wise at 0° C. The resulting mixture was stirred at rt for 1 h.It was concentrated, diluted with DCM (20 mL) and washed with brinesolution (5 mL) and dried over Na₂SO₄. After evaporation of the solvent,the crude product was purified by flash column chromatography to affordthe titled compound. Yield: 77% (0.154 g, brown oil). ¹H NMR (400 MHz,DMSO-d₆): δ 8.29 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76(dd, J=8.0, 1.6 Hz, 1H), 5.99-5.98 (m, 2H), 5.12 (d, J=4.4 Hz, 1H),4.62-4.59 (m, 1H), 3.67 (t, J=5.2 Hz, 4H), 3.39-3.37 (m, 1H), 2.42-2.40(m, 2H), 2.35-2.32 (m, 2H), 1.32-1.27 (m, 6H). LCMS: (Method A) 357.2(M+H), Rt. 2.38 min, 99.04% (Max). HPLC: (Method A) Rt. 2.31 min, 98.15%(Max).

Example 169N-(2-(4-(1-(2-methylbenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

To a stirred solution of Intermediate 10 (0.17 g, 0.66 mmol) in dry DMF(3 mL), TEA (0.45 mL, 1.99 mmol) and Intermediate 26 (0.21 g, 0.99 mmol)were added at rt. The resulting reaction mixture was stirred at 120° C.overnight. It was cooled to rt and concentrated under reduced pressure.The resulting crude product was purified by flash column chromatography,followed by MD Autoprep HPLC (Method B), affording the title product(brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ 9.80 (s, 1H), 8.45 (s, 2H),7.95 (d, J=8.0 Hz, 1H), 7.83 (s, 1H), 7.38 (d, J=8.4 Hz, 1H), 3.58-3.57(m, 5H), 2.78 (s, 3H), 3.36-2.35 (m, 4H), 1.99 (s, 3H), 1.37 (d, J=6.8Hz, 3H). LCMS: (Method A) 397.2 (M+H), Rt. 2.38 min, 98.23% (Max). HPLC:(Method A) Rt. 2.31 min, 96.17% (Max).

Example 170N-(5-(4-(1-(2-methylbenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of Intermediate 7 (0.17 g, 0.64 mmol) in dry DMF(3 mL), TEA (0.3 mL, 1.93 mmol) and Intermediate 26 (0.21 g, 0.96 mmol)were added at rt and the reaction mixture was stirred at 120° C.overnight. The resulting reaction mixture was cooled to rt and thesolvents were concentrated under reduced pressure. The resulting crudeproduct was purified by flash chromatography followed by MD AutoprepHPLC (Method B) affording the title product (brown oil). ¹H NMR (400MHz, DMSO-d₆): δ 12.01 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.84 (d, J=1.6Hz, 1H), 7.39-7.37 (m, 1H), 3.64-3.62 (m, 1H), 3.36-3.33 (m, 4H), 2.79(s, 3H), 2.53-2.52 (m, 2H), 2.49-2.47 (m, 2H), 2.07 (s, 3H), 1.38 (d,J=6.8 Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.45 min, 98.38% (Max).HPLC: (Method A) Rt. 2.32 min, 98.57% (Max).

Example 1712-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

To a stirred solution of 3-hydroxypropionic acid (97 mg, 1.0 mmol) indry NMP (5 mL), Example 132 (300 mg, 0.9 mmol), triethylamine (0.18 mg,1.8 mmol) and HATU (513 mg, 1.3 mmol) were added at 0° C. The resultingmixture was stirred at rt for 1 h. It was diluted with water (15 mL) andextracted with EtOAc (2×15 mL). Combined organic layers was dried overNa₂SO₄. After evaporation of the solvents, the crude product was furtherpurified by MD Autoprep HPLC (Method B), affording the title compound(off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ11.98 (s, 1H), 6.88 (s,1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.98-5.97 (m, 2H),4.71 (t, J=5.2 Hz, 1H), 3.69-3.64 (m, 2H), 3.40-3.32 (m, 5H), 2.54-2.32(m, 6H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method A) 406.0 (M+H), Rt. 2.15min, 99.05% (Max). HPLC: (Method A) Rt. 2.11 min, 98.88% (Max).

Example 1726-(1-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

To the stirred solution of Intermediate 11 (0.25 g, 1.03 mmol) in dryDMF (3 mL), TEA (0.43 mL, 3.09 mmol) and 2-chloro-5-fluoropyrimidine(0.15 g, 1.13 mmol) were added at rt and the resulting mixture wasstirred at 120° C. overnight. It was cooled to rt and solvent wasevaporated under reduced pressure. The resulting crude product waspurified by flash chromatography to afford the title product (brownoil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93-8.91 (m, 2H), 8.41 (s, 2H), 8.07(d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 3.75-3.74 (m,1H), 3.68-3.65 (m, 4H), 2.56-2.53 (m, 2H), 2.42-2.41 (m, 2H), 1.42 (d,J=6.8 Hz, 3H). LCMS: (Method A) 339.0 (M+H), Rt. 2.32 min, 99.29% (Max).HPLC: (Method A) Rt. 2.23 min, 99.19% (Max).

Example 173(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-fluoropyrimidine

To a stirred solution of Intermediate 16 (0.4 g, 1.50 mmol) in dry DMF(10 mL), TEA (0.6 mL, 4.5 mmol) and 2-chloro-5-fluoro pyrimidine (0.2 g,1.5 mmol) were added at rt and the reaction mixture was stirred at 90°C. for 12 h. It was cooled to rt and concentrated. Dichloromethane (50mL) was added and the mixture was washed with sat NaCl solution (10 mL)dried over anhydrous Na₂SO₄. After evaporation of the solvents, thecrude product was purified by flash chromatography to give the titlecompound (colourless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.42 (s, 2H),7.43 (d, J=7.6 Hz, 1H), 6.89-6.85 (m, 1H), 6.75 (dd, J=7.6, 1.2 Hz, 1H),5.99-5.98 (m, 2H), 3.65 (t, J=5.2 Hz, 4H), 3.37-3.35 (m, 1H), 2.43-2.41(m, 2H), 2.37-2.35 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A)331.0 (M+H), Rt. 2.88 min, 99.79% (Max). HPLC: (Method A) Rt. 2.82 min,99.93% (Max).

Example 174N-(2-(4-(1-(benzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

SGN020494-01-00045-078N01:

To a stirred solution of Intermediate 10 (0.22 g, 0.85 mmol) in dry DMF(10 mL), DIPEA (0.6 mL, 3.43 mmol) and Intermediate 27 (0.25 g, 1.28mmol) were added at rt and the reaction mixture was stirred overnight at120° C. It was cooled to rt and the solvent was evaporated under reducedpressure. The resulting crude product was purified by flash columnchromatography to afford the title product (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 9.81 (s, 1H), 9.35 (s, 1H), 8.46 (s, 2H), 8.11 (s,1H), 8.04 (d, J=8.4 Hz, 1H), 7.55-7.53 (m, 1H), 3.65-3.62 (m, 5H),2.52-2.51 (m, 2H), 2.34-2.33 (m, 2H), 2.00 (s, 3H), 1.39 (d, J=6.4 Hz,3H). LCMS: (Method A) 383.3 (M+H), Rt. 2.03 min, 98.47% (Max). HPLC:(Method A) Rt. 1.98 min, 98.35% (Max).

Example 175(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-bromopyrimidine

To a stirred solution of Intermediate 16 (4.1 g, 15.5 mmol) in dry DMF(30 mL), TEA (6.4 mL, 46.5 mmol) and 5-bromo-2-chloro pyrimidine (3 g,15.5 mmol) were added at rt and the reaction mixture was stirred at 90°C. for 12 h. It was cooled to rt and concentrated under reducedpressure. Dichloromethane (150 mL) was added. The solution was washedwith brine (50 mL) and dried over anhydrous Na₂SO₄. After evaporation ofthe solvents, the crude product was purified by flash chromatographyaffording the title compound. Yield: 57% (3.5 g, white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.43 (s, 2H), 6.83-6.89 (m, 2H), 6.76 (d, J=7.8Hz, 1H), 5.99-5.98 (m, 2H), 3.67 (t, J=4.8 Hz, 4H), 3.37-3.33 (m, 1H),2.41-2.33 (m, 4H), 1.28 (d, J=6.6 Hz, 3H). LCMS: (Method A) 391.0 (M+H),Rt. 3.25 min, 99.9% (Max).

Example 176(S)-2-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)propan-2-ol

To a stirred solution of Example 175 (0.5 g, 1.28 mmol) in dry THF (10mL) cooled at −78° C., n-BuLi (1.6 M, 1.2 mL, 19.2 mmol, Aldrich) wasadded. The mixture was stirred at −78° C. for 1 h. Dry acetone in THF(0.89 g, 1.53 mmol, Aldrich) was then added at the same temperature andthe mixture was stirred for 10 minutes. The temperature was increased tort over 1 h. The reaction mixture was quenched with saturated ammoniumchloride solution (10 mL). The desired product was extracted with EtOAc(50 mL), washed with sat NaCl solution (20 mL) and dried over anhydrousNa₂SO₄. After evaporation of the solvents, the crude product waspurified by MD Autoprep HPLC (Method D), affording the title product(off white solid). ¹H NMR (400 MHz, DMSO-d₆): 8.33 (s, 2H), 6.89-6.83(m, 2H), 6.77-6.74 (m, 1H), 5.99-5.98 (m, 2H), 5.05 (s, 1H), 3.66 (d,J=4.8 Hz, 4H), 3.38-3.35 (m, 1H), 2.45-2.43 (m, 2H), 2.35-2.32 (m, 2H),1.59 (s, 6H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 371.2 (M+H), Rt.2.5 min, 99.51% (Max). HPLC: (Method A) Rt. 2.46 min, 98.9% (Max).

Example 177(S)-N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-3-hydroxypropanamide

Step 1:(S)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-nitropyrimidine

To a stirred solution of Intermediate 16 (4.8 g, 18.7 mmol) in dry ACN(15 mL), Et₃N (10.5 mL, 75.0 mmol) and 2-chloro-5-nitropyrimidine (3.0g, 18.7 mmol) were added at rt. The mixture was heated at 80° C.overnight. It was cooled to rt, diluted with DCM (20 mL), washed withwater (15 mL) and brine (15 mL), and dried over anhydrous Na₂SO₄. Afterevaporation of the solvents, the crude product was triturated with MeOH,filtered and dried under vacuum, affording the title compound. Yield:75% (3.8 g, pale yellow solid). LCMS: (Method A) 358.3 (M+H), Rt.2.94min, 98.07% (Max).

Step 2:(S)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-amine

To a stirred solution of(S)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-nitropyrimidineobtained in the previous step (1.0 g, 62.9 mmol) in a mixture ofmethanol (100 mL) and THF (100 mL), 10% Pd/C (200 mg, 20% w/w) was addedat rt. The reaction mixture was stirred under hydrogen atmosphere (1kg/cm²) at rt overnight. Completion of the reaction was confirmed byTLC. The reaction mixture was filtered through celite and washed withmethanol. After evaporation of the solvents, the title compound wasobtained and used in the next step without further purification. Yield:96% (1.0 g, pale brown solid). LCMS: (Method A) 328.2 (M+H), Rt. 1.52min, 90.58% (Max).

Step 3:(S)-N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-3-hydroxypropanamide

To a stirred solution of 3-hydroxypropionic acid (132 mg, 1.0 mmol) indry DMF (2 mL),(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-amineobtained in the previous step (400 mg, 1.2 mmol), DIPA (236 mg, 1.83mmol) and HATU (557 mg, 1.83 mmol) were added at 0° C. The reactionmixture was stirred at rt overnight. The completion of the reaction wasmonitored by TLC. The reaction mixture was diluted water (10 mL) andextracted with DCM (15 mL). The organic layer was dried over anhydrousNa₂SO₄ and evaporated. The crude product was purified by preparativeHPLC (Method B), affording the title product (off white solid). ¹H NMR(400 MHz, CDCl₃): δ 8.40 (s, 2H), 7.79 (br s, 1H), 6.88 (s, 1H), 6.75(s, 2H), 5.96-5.95 (m, 2H), 3.97 (t, J=6.8 Hz, 2H), 3.77 (t, J=4.8 Hz,4H), 3.35 (q, J=6.8 Hz, 1H), 2.56-2.62 (m, 2H), 2.48-2.55 (m, 2H),2.42-2.51 (m, 2H), 1.37 (d, J=6.8 Hz, 3H). LCMS: (Method A) 400.2 (M+H),Rt. 2.11 min, 99.42% (Max). HPLC: (Method A) Rt. 2.06 min, 98.9% (Max).

Example 1782-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

To a stirred solution of Intermediate 25 (0.7 g, 2.57 mmol) in dry DMF(10 mL), TEA (1.1 mL, 7.71 mmol) and Intermediate 6 (0.49 g, 2.57 mmol)were added at rt and the reaction mixture was stirred at 90° C.overnight. The reaction mixture was cooled to rt and concentrated. Water(50 mL) was added and the desired product was extracted with DCM (150mL) and dried over anhydrous Na₂SO₄. After evaporation of the solvents,the crude product was purified by MD Autoprep HPLC (Method B), affordingthe title compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94(d, J=6.0 Hz, 2H), 8.09 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J=8.4Hz, 1H), 7.73 (s, 1H), 3.83-3.82 (m, 1H), 3.49-3.47 (m, 4H) 2.70-2.67(m, 2H), 2.60-2.58 (m, 2H), 2.51-2.49 (m, 4H), 1.42 (d, J=6.8 Hz, 3H).LCMS: (Method A) 395.2 (M+H), Rt. 1.74 min, 99.66% (Max). HPLC: (MethodA) Rt. 1.70 min, 99.19% (Max).

Example 179N-(5-(4-(1-(benzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of Intermediate 7 (0.22 g, 0.83 mmol) in dry DMF(3 mL), DIPEA (0.6 mL, 3.34 mmol) and Intermediate 27 (0.25 g, 1.25mmol) were added at rt. The reaction mixture was stirred at 120° C.overnight. It was cooled to rt and DMF was evaporated under reducedpressure. The resulting crude product was purified by flashchromatography followed by MD Autoprep HPLC (Method B), affording thetitle product (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.34 (s,1H), 8.10 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H),3.63-3.61 (m, 1H), 3.29-3.28 (m, 4H), 2.56-2.53 (m, 2H), 2.43-2.42 (m,2H), 1.93 (s, 3H), 1.37 (d, J=6.8 Hz, 3H). LCMS: (Method A) 389.0 (M+H),Rt. 2.04 min, 96.53% (Max). HPLC: (Method A) Rt. 1.93 min, 97.68% (Max).

Example 180(S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)cyclohexan-1-ol

To a stirred solution of Example 175 (0.5 g, 1.28 mmol) in dry THF (10mL) at −78° C., n-BuLi (1.6M, 0.9 mL, 15.3 mmol, Aldrich) was added andthe reaction mixture was stirred at −78° C. for 1 h. Cyclohexanone (0.15g, 1.53 mmol, Aldrich) in dry THF (1 mL) was added at −78° C. and themixture was stirred for 10 minutes. The temperature was increased to rtover 1 h. The reaction completion was monitored by TLC. The reaction wasquenched with saturated ammonium chloride solution (10 mL) and wasextracted with EtOAc (50 mL). The organic layer was washed with sat NaClsolution (20 mL) dried over anhydrous Na₂SO₄ and the solvents wereevaporated under reduced pressure. The crude product was purified byflash column chromatography to afford the title compound (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.38 (s, 2H), 6.88 (s, 1H), 6.83(d, J=7.6 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 5.98-5.97 (m, 2H), 4.73 (s,1H), 3.65-3.63 (m, 4H), 3.33-3.31 (m, 1H), 2.40-2.38 (m, 2H), 2.34-2.32(m, 2H), 1.65-1.60 (m, 6H), 1.45-1.42 (m, 2H), 1.28-1.22 (m, 5H). LCMS:(Method A) 411.2 (M+H), Rt. 3.25 min, 96.51% (Max). HPLC: (Method A) Rt.3.14 min, 97.88% (Max).

Example 181(S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)cyclopentan-1-ol

The title compound was prepared according to the protocol described forthe preparation of Example 180, replacing cyclohexanone withcyclopentanone (0.12 g, 1.53 mmol, Aldrich). The crude product waspurified by flash column chromatography to afford the title compound(brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.38 (s, 2H), 6.88 (s, 1H),6.83 (d, J=7.6 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 5.98-5.97 (m, 2H), 4.80(s, 1H), 3.65-3.63 (m, 4H), 3.32-3.30 (m, 1H), 2.49-2.45 (m, 2H),2.34-2.32 (m, 2H), 1.82-1.7 (m, 8H), 1.28 (d, J=6.8 Hz, 3H). LCMS:(Method A) 397.2 (M+H), Rt. 2.90 min, 98.83% (Max). HPLC: (Method A) Rt.2.87 min, 99.10% (Max).

Example 182(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

Step 1:tert-butyl-4-((trimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate

To a stirred solution of N-boc piperidone (5 g, 25.09 mmol) in dry DMF(50 mL), TEA (6.95 mL, 50.18 mmol) and trimethylsilyl chloride (6.35 mL,50.18 mmol) were added slowly at 0° C. and the mixture was stirred at90° C. overnight. Solvents were evaporated under reduced pressure andEtOAc (70 mL) was added. This solution was washed with water (25 mL),10% sodium bicarbonate solution (25 mL), (15 mL) and was dried overNa₂SO₄. Solvents were evaporated, affording the title product that wasused in the next step without further purification. Yield: 99% (7.49 g,brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ 4.80 (s, 1H), 3.62-3.59 (m,2H), 3.44-3.41 (m, 2H), 2.02-2.00 (m, 2H), 1.40 (s, 9H), 0.17 (s, 9H).

Step 2: tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate

To a stirred solution oftert-butyl-4-((trimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate,obtained in step 1, (7.48 g, 27.60 mmol) in dry CCl₄ (80 mL, 10 V),N-bromosuccinimide (5.42 g, 30.36 mmol) was added at 10° C. The reactionmixture was stirred at 10-15° C. for 2 h. It was evaporated underreduced pressure. Water (30 mL) was added and the desired product wasextracted with EtOAc (2×60 mL). Organic layer was dried over Na₂SO₄ andthe solvents were evaporated. The resulting crude product was purifiedby flash chromatography affording the title product (white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 4.74 (s, 1H), 4.02-4.00 (m, 2H), 3.60-3.58 (m,2H), 2.69-2.68 (m, 2H), 1.39 (s, 9H).

Step 3:(S)-4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine-1-carbothioamide

To stirred solution of Intermediate 16 (5 g, 18.51 mmol) in THF (50 mL),TEA (8.8 mL, 55.55 mmol) followed by N,N′-thiocarbonyldiimidazole (3.8g, 22.22 mmol, Arbor chemicals) were added at rt and the mixture wasstirred overnight at rt. Ammonia solution in methanol (7 N, 50 mL, 350mmol) was added and the mixture was stirred overnight at 50° C. It wasevaporated under reduced pressure, diluted with EtOAc (100 mL), washedwith water (25 mL) and dried over Na₂SO₄. The title product was obtainedafter evaporation of the solvents and was used without furtherpurification. Yield: 58% (3.6 g, brown liquid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.61 (s, 2H), 6.99 (s, 1H), 6.70 (d, J=8.0 Hz, 2H),5.97-5.96 (m, 2H), δ 3.67-3.65 (m, 1H), 3.40-3.37 (m, 2H), 2.77-2.75 (m,2H), 2.33-2.25 (m, 4H), 1.24-1.22 (m, 3H). LCMS: (Method A) 294.00(M+H), Rt. 2.03 min, 55.70% (Max).

Step 4:tert-butyl(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a stirred solution of(S)-4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine-1-carbothioamide(Example 182, Step 3, 3.6 g, 12.28 mmol) in isopropanol (35 mL),tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (Example 182, Step 2,3.4 g, 12.28 mmol) was added at rt. The reaction mixture was stirredovernight at 90° C. After evaporation of the solvents, the crude productwas purified by flash column chromatography to afford the title product(yellow liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.88-6.87 (m, 2H), 6.85(s, 1H), 5.99-5.98 (m, 2H), 4.35-4.34 (m, 1H), 4.06-4.04 (m, 2H),3.57-3.56 (m, 2H), 3.42-3.41 (m, 2H), δ 3.32-3.29 (m, 2H), 2.49-2.46 (m,2H), 2.41-2.40 (m, 4H), 1.42 (s, 9H), 1.24-1.22 (m, 3H). LCMS: (MethodA) 473.0 (M+H), Rt. 3.54 min, 71.96% (Max).

Step 5:(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

To a stirred solution oftert-butyl(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylateobtained in previous step (1.7 g, 3.60 mmol) in 1,4-dioxane (17 mL), HClin dioxane (4 N, 40 mmol, 10 mL, 6V) was added at 0° C. The reactionmixture was stirred for 2 h at rt. It was concentrated under reducedpressure. DCM was added (15 mL) and was evaporated. This process wasrepeated a second time. Saturated sodium bicarbonate solution (20 mL)was added and the mixture was stirred for 2 h. Resulting free amine wasextracted with DCM (100 mL), washed with brine (15 mL) and dried overNa₂SO₄. After evaporation of the solvent, the resulting crude productwas purified by flash column chromatography to afford the title compound(brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ 6.88 (d, J=1.2 Hz, 1H),6.85-6.83 (m, 1H), 6.76-6.74 (m, 1H), 5.99-5.98 (m, 2H), 3.68 (s, 2H),3.42-3.40 (m, 1H), 3.30-3.27 (m, 4H), 2.91 (t, J=5.6 Hz, 4H), 2.40-2.38(m, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 373.3 (M+H), Rt. 1.82min, 99.52% (Max). HPLC: (Method A) Rt. 1.80 min, 99.18% (Max).

Example 183 Ethyl(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)nicotinate

To a stirred solution of Intermediate 16 (1.0 g, 3.71 mmol) in dry DMF(10 mL), TEA (1.54 mL, 11.1 mmol) and ethyl-6-chloro nicotinate (0.69 g,3.71 mmol) were added at rt and the reaction mixture was heated at 90°C. for 12 h. It was cooled to rt and concentrated. DCM (50 mL) was addedand the resulting solution was washed with brine (30 mL) and dried overanhydrous Na₂SO₄. After evaporation of the solvents, the crude productwas purified by flash chromatography to give the title compound (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.61 (d, J=2.4 Hz, 1H),7.92-7.90 (m, 1H), 6.89 (d, J=1.6 Hz, 1H), 6.85-6.81 (m, 2H), 6.77-6.75(m, 1H), 5.99-5.98 (m, 2H), 4.27 (q, J=7.2 Hz, 2H) 3.61 (t, J=4.8 Hz,4H), 3.39-3.37 (m, 1H), 2.45-2.33 (m, 5H), 1.29-1.26 (m, 3H). LCMS:(Method A) 384.2 (M+H), Rt. 3.14 min, 98.30% (Max). HPLC: (Method A) Rt.3.11 min, 98.88% (Max).

Example 184(S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one

To a stirred solution of Example 182 (0.18 g, 0.48 mmol) in dry DCM (2mL), TEA (0.13 mL, 0.96 mmol) and acetic anhydride (0.07 mL, 0.72 mmol)were added at 0° C. and the reaction mixture was stirred at rtovernight. It was diluted with DCM (50 mL), washed with water (15 mL),brine (15 mL) and dried over anhydrous Na₂SO₄. After evaporation of thesolvents, the crude product was purified by flash chromatography to givethe title compound (brown oil). ¹H NMR (400 MHz, DMSO-d₆, performed at80° C.): δ 6.87 (d, J=1.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (dd,J=1.6, 8.0 Hz, 1H), 5.99-5.98 (m, 2H), 4.48 (s, 2H), 3.71-3.65 (m, 2H),3.47-3.43 (m, 1H), 3.35-3.30 (m, 4H), 2.60-2.54 (m, 2H), 2.47-2.40 (m,4H), 2.06 (s, 3H), 1.29 (d, J=6.4 Hz, 3H). LCMS: (Method A) 415.3 (M+H),Rt. 2.20 min, 96.80% (Max). HPLC: (Method A) Rt 2.15 min, 97.88% (Max).

Example 185(S)-(6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyridin-3-yl)methanol

To a stirred solution of Example 183 (0.2 g, 0.56 mmol) in dry MeOH (5mL) cooled at 0° C., was added lithium aluminium hydride (2.4 M, 0.24mL, 1.17 mmol, spectrochem) dropwise and the mixture was stirred for 1 hat the same temperature. The reaction mixture was quenched withsaturated ammonium chloride (5 mL) and extracted with ethyl acetate (20mL). The organic phase was washed with brine solution (5 mL), dried overNa₂SO₄ and concentrated. The crude product was purified by flash columnchromatography to afford the titled compound. Yield: 66% (88 mg,colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.04 (d, J=2.0 Hz, 1H),7.46 (dd, J=8.8, 2.4 Hz, 1H), 6.88-6.86 (m, 1H), 6.84-6.82 (m, 1H),6.76-6.73 (m, 2H), 5.98-5.97 (m, 2H), 4.96 (t, J=5.6 Hz, 1H) 4.32 (d,J=5.6 Hz, 2H), 3.41 (t, J=9.6 Hz, 4H), 3.34-3.32 (m, 1H), 2.49-2.45 (m,2H), 2.39-2.37 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 342.3(M+H), Rt. 1.74 min, 99.28% (Max). HPLC: (Method A) Rt. 1.71 min, 98.49%(Max).

Example 186(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylnicotinamide

Step 1: Lithium(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)nicotinate

Example 183 (1 g, 2.62 mmol) was dissolved in a mixture of MeOH (2 mL),THF (7 mL) and water (1 mL). The resulting mixture was cooled to 0° C.and lithium hydroxide (0.32 g, 7.86 mmol, spectrochem) was added. Theresulting mixture was heated at 90° C. for 2 h. It was then concentratedand used as such in next step. Yield: 85% (0.8 g, off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 8.52 (d, J=2.3 Hz, 1H), 7.89-7.86 (m, 1H),6.88-6.59 (m, 4H), 5.97-5.96 (m, 2H), 3.43-3.33 (m, 5H), 2.36-2.28 (m,4H), 1.26 (d, J=8.7 Hz, 3H). LCMS: (Method A) 354.0 (M+H), Rt. 3.639min, 93.32% (Max).

Step 2:(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylnicotinamide

To a stirred solution of lithium(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)nicotinate(0.3 g, 8.32 mmol) in dry DCM (10 mL) cooled to 0° C., were addedtriethylamine (0.5 mL, 3.72 mmol), methylamine in THF (2 M, 2 mL, 2.24mmol) followed by T₃P (0.6 mL, 3.72 mmol). The resulting mixture wasstirred at rt for 1 h. Reaction completion was monitored by TLC. Thereaction mixture was washed with 10% sodium bicarbonate solution (10mL). The organic layer was dried over Na₂SO₄, and evaporated to dryness.The crude product was purified by flash column chromatography (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.54 (d, J=2.0 Hz, 1H), 8.18 (d,J=4.4 Hz, 1H), 7.89 (dd, J=2.4, 9.2 Hz, 1H), 6.89 (d, J=1.2 Hz, 1H),6.85-6.77 (m, 1H), 6.77-6.74 (m, 2H), 5.99-5.98 (m, 2H), 3.54 (t, J=4.8Hz, 4H), 3.37-3.35 (m, 1H), 2.73 (d, J=4.4 Hz, 3H), 2.45-2.43 (m, 2H),2.39-2.32 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 369.2 (M+H),Rt. 2.05 min, 98.6% (Max). HPLC: (Method A) Rt. 2.00 min, 98.3% (Max).

Example 187(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylnicotinamide

To a stirred solution of lithium(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)nicotinate(Example 186, Step 1, 0.5 g, 1.38 mmol) in dry DCM (10 mL) at 0° C.,were added triethylamine (2.6 mL, 4.14 mmol), dimethylamine in THF (2 M,2 mL, 2.24 mmol) followed by T₃P (2.6 mL, 4.14 mmol). The resultingmixture was stirred at rt for 1 h. Reaction completion was monitored byTLC. The reaction mixture was washed with 10% sodium bicarbonatesolution (10 mL). The organic layer was dried over Na₂SO₄, andevaporated to dryness. The crude product was purified by flash columnchromatography. Yield: 52% (279 mg, off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.19 (d, J=2.4 Hz, 1H), 7.59 (dd, J=2.4, 8.8 Hz, 1H), 6.90(s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.78 (t, J=7.2 Hz, 2H), 5.99-5.98 (m,2H), 3.54-3.51 (m, 4H), 3.38-3.33 (m, 1H), 2.96 (s, 6H), 2.47-2.46 (m,2H), 2.41-2.34 (m, 2H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 383.3(M+H), Rt. 2.19 min, 99.8% (Max). HPLC: (Method A) Rt. 2.14 min, 99.6%(Max).

Example 188(S)-4-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-ol

To a stirred solution of Example 175 (0.5 g, 1.28 mmol) in dry THF (10mL) at −78° C. was added n-BuLi (1.6 M, 1.2 mL, 1.92 mmol, Aldrich) andthe resulting mixture was stirred to −78° C. for 1 h.Tetrahydrofuran-4H-pyran-4-one (0.15 g, 1.53 mmol, Aldrich) in THF (5mL) was added at −78° C. for 10 minutes. The temperature was increasedto rt over 1 h. The reaction completion was monitored by TLC. Thereaction mixture was quenched with saturated ammonium chloride solution(10 mL). It was extracted with EtOAc (50 mL). The organic phase waswashed with saturated NaCl solution (20 mL) and dried over anhydrousNa₂SO₄. The crude product was purified by flash column chromatography toafford the title compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆):δ 8.42 (s, 2H), 6.90 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz,1H), 5.99-5.98 (m, 2H), 5.07 (s, 1H), 3.77-3.66 (m, 8H), 3.39-3.37 (m,1H), 2.44-2.40 (m, 2H), 2.37-2.33 (m, 2H), 1.95-1.87 (m, 2H), 1.57-1.54(m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 413.3 (M+H), Rt. 2.32min, 99.65% (Max). HPLC: (Method A) Rt. 2.27 min, 99.23% (Max).

Example 1893-(2-(4-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)tetrahydrofuran-3-ol

Example 189 was prepared according the same procedure as Example 188,replacing tetrahydrofuran-4H-pyran-4-one with dihydrofuan(2H)-one (0.13g, 1.53 mmol, Aldrich). The crude product was purified by flash columnchromatography to afford the title compound (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.41 (s, 2H), 6.90 (d, J=1.2 Hz, 1H), 6.84 (d,J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 5.99-5.98 (m, 2H), 3.97-3.93 (m,2H), 3.78-3.76 (m, 1H), 3.68-3.65 (m, 6H), 2.50-2.42 (m, 1H), 2.35-2.32(m, 4H), 2.33-2.32 (m, 1H), 2.11-2.06 (m, 1H), 1.28 (d, J=6.4 Hz, 3H).LCMS: (Method A) 399.0 (M+H), Rt. 2.32 min, 97.39% (Max). HPLC: (MethodA) Rt. 2.22 min, 97.15% (Max).

Example 190(S)-2-(6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol

To a stirred solution of Example 183 (0.3 g, 0.78 mmol) in dry THF (10mL) at 0° C. was added methyl magnesium bromide solution in THF (1.4 M,0.8 mL, 1.17 mmol, Aldrich). The resulting mixture was stirred at 0° C.for 1 h. The temperature was increased to rt and the mixture was stirred12 h at that temperature. The reaction completion was monitored by TLC.The reaction mixture was quenched with saturated ammonium chloridesolution (10 mL) and extracted with EtOAc (50 mL). The organic layer waswashed with sat NaCl solution (20 mL) and dried over anhydrous Na₂SO₄.The crude product was purified by flash column chromatography, yieldingthe title compound. Yield: 61% (0.178 g, colorless oil). ¹H NMR (400MHz, DMSO-d₆): δ 8.17 (d, J=2.0 Hz, 1H), 7.59-7.57 (m, 1H), 6.89-6.83(m, 2H), 6.78-6.70 (m, 2H), 5.99-5.98 (m, 2H), 4.92 (s, 1H), 3.39 (t,J=4.8 Hz, 5H), 2.40-2.36 (m, 4H), 1.39 (s, 6H), 1.29 (d, J=6.8 Hz, 3H).LCMS: (Method A) 370.2 (M+H), Rt. 1.94 min, 99.3% (Max). HPLC: (MethodA) Rt. 1.92 min, 99.60% (Max).

Example 191(S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-bromopyridin-2-yl)piperazine

To a stirred solution of Intermediate 16 (5.5 g, 20.68 mmol) in dry DMF(50 mL), TEA (7.1 mL, 51.45 mmol) and 5-bromo-2-fluoropyridine (3 g,17.24 mmol) were added at rt and the reaction mixture was stirred at 90°C. overnight. The reaction mixture was cooled to rt and concentratedunder reduced pressure. Water (30 mL) was added and the compound wasextracted with EtOAc (100 mL). The organic layer was dried overanhydrous Na₂SO₄ and concentrated. The resulting crude product waspurified by flash chromatography to afford the title compound (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.14 (d, J=2.4 Hz, 1H), 7.66-7.65(m, 1H), 6.87 (d, J=1.2 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.77-6.55 (m,2H), 5.99-5.98 (m, 2H), 3.43 (t, J=4.8 Hz, 4H), 3.36-3.34 (m, 1H),2.47-2.45 (m, 2H), 2.38-2.35 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS:(Method A) 392.0 (M+H), Rt. 3.32 min, 99.88% (Max). HPLC: (Method A) Rt.3.26 min, 99.96% (Max).

Example 192(S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-(methylthio)pyridin-2-yl)piperazine

To a stirred solution of Example 191 (3.0 g, 7.71 mmol) in dry THF (30mL), n-BuLi (6.0 mL, 9.2 mmol) was added at −78° C. and stirred for 1 h.Dimethyl disulphide (45 mL) was added at same temperature and stirredfor 1 h at rt. The reaction mixture was quenched with saturated NH₄Cland extracted with EtOAc. The organic layer was washed with water anddried over anhydrous Na₂SO₄ and concentrated. The resulting crude waspurified by flash column chromatography to afford the title compound.Yield: 90% (2.58 g, yellow solid). ¹H NMR (400 MHz, CDCl₃): δ 8.21 (d,J=2.4 Hz, 1H), 7.52-7.51 (m, 1H), 6.89 (s, 1H), 6.76 (s, 2H), 6.56 (d,J=8.8 Hz, 1H), 5.96-5.94 (m, 2H), 3.52 (m, 4H), 3.34 (d, J=6.0 Hz, 1H),2.57-2.50 (m, 4H), 2.38 (s, 3H), 1.36 (d, J=6.4 Hz, 3H). LCMS: (MethodA) 358.3.0 (M+H), Rt. 2.61 min, 97.99% (Max). HPLC: (Method A) Rt. 2.56min, 97.57% (Max).

Example 193(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-(methylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

To a stirred solution of Example 182 (0.1 g, 0.26 mmol) in dry DCM (5mL), TEA (0.07 mL, 0.54 mmol) and methane sulfonyl chloride (0.22 mL,0.29 mmol) were added at 0° C. and the reaction mixture was stirred atrt for 1 h. The resulting reaction mixture was diluted with DCM (50 mL)and washed with 10% sodium bicarbonate solution (15 mL), water (15 mL)and brine (15 mL). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated. The resulting crude product was purified by flash columnchromatography to afford the title compound (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 6.87 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H),6.76 (d, J=8.0 Hz, 1H), 5.99-5.98 (m, 2H), 4.26 (s, 2H), 3.46-3.44 (m,2H), 3.41-3.39 (m, 1H), 2.98-2.93 (m, 3H), 2.67-2.65 (m, 4H), 2.54-2.52(m, 2H), 2.39-2.38 (s, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A)451.2 (M+H), Rt. 2.46 min, 98.64% (Max). HPLC: (Method A) Rt. 2.56 min,97.91% (Max).

Example 194(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-d]pyridine

To a stirred solution of Example 182 (0.1 g, 2.61 mmol) in dry THF (2mL), sodium triacetoxy borohydride (0.17 g, 8.06 mmol) and formaldehyde(0.05 mL, 5.37 mmol, 40% solution in water) were added at rt and thereaction mixture was stirred at this temperature overnight. The reactionmixture was diluted with EtOAc (30 mL) and was washed with water (5 mL),brine (5 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The resulting crude product was purified by flash columnchromatography to afford the title compound (brown oil). ¹H NMR (400MHz, DMSO-d₆): δ 6.88 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 5.97 (m, 2H), 3.38-3.36 (m, 5H), 3.30-3.27 (m, 4H), 2.62-2.60(m, 2H), 2.46-2.44 (m, 2H), 2.40-2.38 (m, 2H), 2.32 (s, 3H), 1.27 (d,J=6.8 Hz, 3H). LCMS: (Method A) 387.2 (M+H), Rt. 1.84 min, 99.86% (Max).HPLC: (Method A) Rt. 1.85 min, 99.51% (Max).

Example 195(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-methoxypyrimidine

To a stirred solution of Intermediate 16 (0.55 g, 2.07 mmol) in dry DMF(5 mL), triethylamine (0.9 mL, 6.21 mmol, spectrochem) and2-chloro-5-methoxy pyrimidine (0.3 g, 2.07 mmol, Combi-Blocks) wereadded and the resulting mixture was heated to 90° C. for 12 h. Thereaction mixture was cooled down to rt and concentrated. Dichloromethane(25 mL) was added and the resulting solution was washed with water (20mL), brind (20 mL) and dired over Na₂SO₄. After evaporation of thesolvents, the crude product was purified by flash column chromatographyto afford the title compound (brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ8.18 (s, 2H), 6.87 (m, 2H), 6.76 (d, J=8.0 Hz, 1H), 5.99-5.98 (m, 2H),3.76 (s, 3H), 3.58 (t, J=4.8 Hz, 4H), 3.38-3.36 (m, 1H), 2.45-2.42 (m,2H), 2.36-2.33 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 343.2(M+H), Rt. 2.73 min, 99.83% (Max). HPLC: (Method A) Rt. 2.71 min, 99.41%(Max).

Example 196(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-methoxypyrimidine

To a stirred solution of Intermediate 11 (0.2 g, 0.8 mmol) in dry DMF (2mL), triethylamine (0.57 mL, 4.0 mmol, spectrochem) and2-chloro-5-methoxy pyrimidine (0.14 g, 0.9 mmol, Combi-Blocks) wereadded and the resulting mixture was heated at 90° C. overnight. Thereaction mixture was cooled down to rt and concentrated. Dichloromethane(25 mL) was added and the resulting mixture was washed with water (20mL), brine (20 mL) and dried over Na₂SO₄. After evaporation of thesolvents, the crude product was purified by flash chromatography toafford the title compound (gray solid). ¹H NMR (400 MHz, DMSO-d₆): δ8.93-8.91 (m, 2H), 8.17 (s, 2H), 8.07 (d, J=8.8 Hz, 1H), 7.99 (s, 1H),7.90 (d, J=8.8 Hz, 1H), 3.75-3.74 (m, 1H), 3.74 (s, 3H), 3.62-3.60 (m,4H), 2.52-2.49 (m, 4H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 351.0(M+H), Rt. 2.38 min, 99.86% (Max). HPLC: (Method A) Rt. 2.17 min, 98.71%(Max).

Example 197 and 198(S)-1-(2-(4-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-oland(S)-1-(2-(4-((R)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol

Example 168 was submitted to chiral preparative HPLC Method PK toseparate both enantiomers. The first eluting compound was concentratedto give Example 198 (brown oil). ¹H NMR (400 MHz, DMSO d₆): δ 8.29 (s,2H), 6.89 (s, 1H), 6.84 (d, J=7.9 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H),5.99-5.98 (m, 2H), 5.12 (d, J=4.4 Hz, 1H), 4.62-4.61 (m, 1H), 3.67-3.65(m, 4H), 3.38-3.36 (m, 1H), 2.51-2.33 (m, 4H), 1.31 (d, J=6.4 Hz, 3H),1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 357.2 (M+H), Rt. 2.30 min,99.37% (Max). HPLC: (Method A) Rt. 2.30 min, 98.05% (Max). Chiral HPLC:(Method H) Rt. 7.06 min, 100%. The second eluting compound wasconcentrated to give Example 197 (brown oil). ¹H NMR (400 MHz, DMSO d₆):δ 8.29 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz,1H), 5.99-5.98 (m, 2H), 5.11 (d, J=4.4 Hz, 1H), 4.62-4.59 (m, 1H),3.68-3.65 (m, 4H), 3.38-3.36 (m, 1H), 2.35-2.32 (m, 4H), 1.31 (d, J=6.4Hz, 3H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 357.2 (M+H), Rt. 2.29min, 99.93% (Max). HPLC: (Method N) Rt. 2.26 min, 99.62% (Max). ChiralHPLC: (Method H) Rt 7.60 min, 100%.

Example 1991-(4-Bromo-3-methoxyphenyl)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazine

To a stirred solution of Intermediate 4 (0.3 g, 1.056 mmol) in DMSO (6mL), Cs₂CO₃ (1.38 g, 4.22 mmol) and 3-bromo-6-chloro-2-methoxypyridine(0.258 g, 1.16 mmol) were added at rt and the mixture was heated to 120°C. for 12 h. It was diluted with water (10 mL), extracted with EtOAc (25mL) and dried over Na₂SO₄. After evaporation of the solvents, the crudeproduct was purified by MD Autoprep (Method B) affording the titleproduct (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.60 (d, J=8.4Hz, 1H), 6.79-6.73 (m, 3H), 6.25 (d, J=8.4 Hz, 1H), 4.21 (s, 4H), 3.80(s, 3H), 3.42-3.32 (m, 5H), 2.55-2.45 (m, 4H), 1.26 (d, J=6.8 Hz, 3H).LCMS: (Method B) 434.0 (M+1), Rt. 7.151 min, 96.67% (Max). HPLC: (MethodB) Rt. 6.24 min, 95.29% (Max).

Example 2001-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-4-(3-methoxyphenyl)piperazine

The title product was prepared according to the protocol described forExample 199, replacing 3-bromo-6-chloro-2-methoxypyridine with2-chloro-6-methoxypyridine. The crude product was purified by MDAutoprep (Method B), affording the title product (brown solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.40 (t, J=8.0 Hz, 1H), 6.78-6.73 (m, 3H), 6.24(d, J=8.0 Hz, 1H), 5.99 (d, J=8.0 Hz, 1H), 4.21 (s, 4H), 3.73 (s, 3H),3.42-3.37 (m, 5H), 2.37-2.32 (m, 4H), 1.26 (d, J=6.8 Hz, 3H). LCMS:(Method B) 356 (M+H), Rt. 6.622 min, 98.55% (Max). HPLC: (Method A) Rt.3.23 min, 96.44% (Max).

Example 2013-Methyl-7-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoline

To a stirred solution of 2-(piperazin-1-yl)pyrimidine (0.16 g, 0.97mmol) in DMF (5 mL), TEA (0.4 mL, 2.9 mmol) and Intermediate 28 (0.3 g,1.46 mmol) were added at room temperature. The reaction mixture wasstirred at 100° C. for 16 h. The reaction completion was confirmed byTLC. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The resulting crude mixture wasdiluted with EtOAc (50 mL), washed with water (10 mL), brine solution(10 mL), dried over anhydrous Na₂SO₄ and concentrated. The crude productwas purified by flash chromatography to afford the title compound (offwhite solid). ¹HNMR (400 MHz, DMSO-d₆): δ 8.75 (d, J=2.0 Hz, 1H), 8.32(d, J=4.8 Hz, 2H), 8.09 (s, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.61 (d, J=10.0Hz, 1H), 6.59 (t, J=4.8 Hz, 1H), 3.72-3.66 (m, 5H), 2.58-2.55 (m, 2H),2.48 (s, 3H), 2.42-2.38 (m, 2H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (MethodA) 334.2 (M+H), Rt. 1.79 min, 99.76% (Max). HPLC: (Method A) Rt 1.73min, 99.84% (Max).

Example 2023-Methyl-7-(1-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethyl)quinolone

To a stirred solution of Intermediate 29 (0.3 g, 1.29 mmol) in DMSO (5mL), TEA (0.56 mL, 3.8 mmol) and Intermediate 28 (0.4 g, 1.94 mmol) wereadded at room temperature and the reaction mixture was stirred at 120°C. for 16 h. The reaction progression was followed by TLC. The reactionmixture was diluted with water (5 mL) and extracted with EtOAc (2×50mL). The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude mass was purified byflash chromatography (gradient used: 1% MeOH in DCM), to afford thetitle compound (colorless gum). ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (d,J=2.0 Hz, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.10 (s, 1H), 8.03 (d, J=7.6 Hz,1H), 7.86 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.16 (dd, J=2.8,7.6 Hz, 1H), 3.68 (q, J=6.8 Hz, 1H), 3.21-3.18 (m, 4H), 2.63-2.60 (m,2H), 2.50-2.48 (m, 5H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 401.2(M+H), Rt. 2.63 min, 99.88% (Max). HPLC: (Method A) Rt 2.57 min, 99.84%(Max).

Example B01 Human O-GlcNAcase Enzyme Inhibition Assay

5 μl of the appropriate concentration of a solution of inhibitor inMcIlvaine's Buffer (pH 6.5) in 2% DMSO (for a dose response curvecalculation) is added into each well of a 384-well plate (Greiner,781900). Then, 20 nM of His-Tagged hOGA and 10 μM of FL-GlcNAc(Fluorescein mono-beta-D-(2-deoxy-2-N-acetyl) glucopyranoside; MarkerGene Technologies Inc, M1485) were added to the 384-well plate for afinal volume of 20 μl. After incubation for 60 min at room temperature,the reaction was terminated by the addition of 10 μL of stop buffer (200mM glycine, pH 10.75). The level of fluorescence (λ_(exc) 485 nm;(λ_(emm) 520 nm) was read on a PHERAstar machine. The amount offluorescence measured was plotted against the concentration of inhibitorto produce a sigmoidal dose response curve to calculate an IC₅₀. Allindividual data was corrected by subtraction of the background (Thiamet3 uM=100% inhibition) whilst 0.5% DMSO was considered as the controlvalue (no inhibition).

Example B02 Pharmacodynamic Model: Total Protein O-GlcNAcylationImmunoassay (RL2 mAb, Meso Scale Electrochemiluminescence (ECL) Assay)

The test compound was administered orally to C57BL/6J mice. At definedtime intervals after compound administration, typically a time rangingbetween 2 and 48 hours, preferably between 4 and 24 hours, mice weresacrificed by decapitation for blood collection and forebraindissection. Right brain hemispheres were placed in 2 ml Precellys tubes,snap frozen in dry ice and stored at −80° C. Left hemispheres wereplaced in 2 ml Eppendorf tubes, snap frozen in dry ice and stored at−80° C. until further processing. Blood samples were collected inSarstedt tubes containing 35 IU of Heparin and kept at 4° C. Aftercentrifugation for 10 min at 3800×g, 4° C., 50 μL of plasma from eachsample was transferred to a 1.5 ml Eppendorf tube and stored at −80° C.

For the preparation of soluble brain protein for the immunoassay thehemispheres were homogenized in ice-cold Cytobuster reagent (71009—MerckMillipore) buffer with protease inhibitor cocktail. After centrifugationfor 15 min at 17000×g at 4° C. the supernatants were transferred intopolycarbonate tubes (1 ml). The supernatants were cleared bycentrifugation for 1 h. at 100000×g, 4° C., and the proteinconcentrations were determined by using the BCA kit (23227—Pierce,Rockford, Ill.) according to the manufacturer's instructions.

Total Protein O-GlcNAcylation Immunoassay:

Samples were randomised and 120 μg/ml (25 μl/well) of soluble brainprotein was directly coated on a Multi-array 96-well high bind plate(L15XB-3 High bind—Meso Scale Discovery) overnight at 4° C. Afterwashing (3× with PBS-T buffer), the plate was blocked with MSD blocker Asolution for 1 h. at room temperature (RT) under agitation. Afterwashing (3× with PBS-T buffer), the plate was incubated with 0.1 μg/mlof a mouse monoclonal antibody directed against O-GlcNAc moieties (RL2;MA1-072—Thermo Scientific) for 1 h. at RT under agitation. For the ECLassay, after washing (3× with PBS-T buffer), 1 μg/ml of a SULFO-TAG™labeled anti-mouse secondary antibody (Meso Scale Discovery) was addedand the plate was incubated for 1 h. at RT under agitation and protectedfrom light. After washing (3× with PBS-T buffer), 150 μl/well of 1× ReadBuffer T was added to the plates before reading on a Sector Imager 6000(Meso Scale Discovery).

Example B03 Pharmaceutical Preparations

-   (A) Injection vials: A solution of 100 g of an active ingredient    according to the invention and 5 g of disodium hydrogen phosphate in    3 l of bi-distilled water was adjusted to pH 6.5 using 2 N    hydrochloric acid, sterile filtered, transferred into injection    vials, lyophilized under sterile conditions and sealed under sterile    conditions. Each injection vial contained 5 mg of active ingredient.-   (B) Suppositories: A mixture of 20 g of an active ingredient    according to the invention was melted with 100 g of soy lecithin and    1400 g of cocoa butter, poured into moulds and allowed to cool. Each    suppository contained 20 mg of active ingredient.-   (C) Solution: A solution was prepared from 1 g of an active    ingredient according to the invention, 9.38 g of NaH₂PO₄.2H₂O, 28.48    g of Na₂HPO₄.12 H₂O and 0.1 g of benzalkonium chloride in 940 ml of    bi-distilled water. The pH was adjusted to 6.8, and the solution was    made up to 1 l and sterilized by irradiation. This solution could be    used in the form of eye drops.-   (D) Ointment: 500 mg of an active ingredient according to the    invention were mixed with 99.5 g of Vaseline under aseptic    conditions.-   (E) Tablets: A mixture of 1 kg of an active ingredient according to    the invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of    talc and 0.1 kg of magnesium stearate was pressed to give tablets in    a conventional manner in such a way that each tablet contained 10 mg    of active ingredient.-   (F) Coated tablets: Tablets were pressed analogously to EXAMPLE E    and subsequently coated in a conventional manner with a coating of    sucrose, potato starch, talc, tragacanth and dye.-   (G) Capsules: 2 kg of an active ingredient according to the    invention were introduced into hard gelatin capsules in a    conventional manner in such a way that each capsule contained 20 mg    of the active ingredient.-   (H) Ampoules: A solution of 1 kg of an active ingredient according    to the invention in 60 l of bi-distilled water was sterile filtered,    transferred into ampoules, lyophilized under sterile conditions and    sealed under sterile conditions. Each ampoule contained 10 mg of    active ingredient.-   (I) Inhalation spray: 14 g of an active ingredient according to the    invention were dissolved in 10 l of isotonic NaCl solution, and the    solution was transferred into commercially available spray    containers with a pump mechanism. The solution could be sprayed into    the mouth or nose. One spray shot (about 0.1 ml) corresponded to a    dose of about 0.14 mg.

The invention claimed is:
 1. A compound,N-(5-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide,which is:

or any of its tautomers, enantiomers or mixtures thereof.
 2. Apharmaceutically acceptable salt of a compound,N-(5-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide,which is:

or any of its tautomers or enantiomers.
 3. The pharmaceuticallyacceptable salt of the compound of claim 2, or any of its tautomers orenantiomers, wherein the pharmaceutically acceptable salt is acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate,bisulfate, bisulfate, bromide, butyrate, camphorate, camphorsulfonate,caprate, caprylate, chloride, chlorobenzoate, citrate, cyclamate,cinnamate, cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, glycolate,fumarate, galacterate, galacturonate, glucoheptanoate, gluconate,glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, or phthalate.